AU2002229859B2 - Chemical derivatives and their use as anti-telomerase agent - Google Patents
Chemical derivatives and their use as anti-telomerase agent Download PDFInfo
- Publication number
- AU2002229859B2 AU2002229859B2 AU2002229859A AU2002229859A AU2002229859B2 AU 2002229859 B2 AU2002229859 B2 AU 2002229859B2 AU 2002229859 A AU2002229859 A AU 2002229859A AU 2002229859 A AU2002229859 A AU 2002229859A AU 2002229859 B2 AU2002229859 B2 AU 2002229859B2
- Authority
- AU
- Australia
- Prior art keywords
- group
- alkyl
- carbon atoms
- compound according
- amino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 239000000126 substance Substances 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims description 64
- 125000004432 carbon atom Chemical group C* 0.000 claims description 38
- 125000000217 alkyl group Chemical group 0.000 claims description 34
- 108010017842 Telomerase Proteins 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 21
- 125000003118 aryl group Chemical group 0.000 claims description 19
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 19
- -1 4-dimethylamino- quinolyl Chemical group 0.000 claims description 18
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 13
- 125000003342 alkenyl group Chemical group 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- 125000005843 halogen group Chemical group 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 125000003282 alkyl amino group Chemical group 0.000 claims description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 11
- 206010028980 Neoplasm Diseases 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 10
- 230000000694 effects Effects 0.000 claims description 9
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 9
- 125000001769 aryl amino group Chemical group 0.000 claims description 8
- 201000011510 cancer Diseases 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- 125000004986 diarylamino group Chemical group 0.000 claims description 8
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 7
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
- 108091081406 G-quadruplex Proteins 0.000 claims description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 230000002401 inhibitory effect Effects 0.000 claims description 6
- 230000001225 therapeutic effect Effects 0.000 claims description 6
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical group C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 claims description 5
- 125000004429 atom Chemical group 0.000 claims description 5
- PXXJHWLDUBFPOL-UHFFFAOYSA-N benzamidine Chemical compound NC(=N)C1=CC=CC=C1 PXXJHWLDUBFPOL-UHFFFAOYSA-N 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- 229910052705 radium Inorganic materials 0.000 claims description 5
- 229910052701 rubidium Inorganic materials 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 238000011282 treatment Methods 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- XNCOSPRUTUOJCJ-UHFFFAOYSA-N Biguanide Chemical compound NC(N)=NC(N)=N XNCOSPRUTUOJCJ-UHFFFAOYSA-N 0.000 claims description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 4
- 125000004414 alkyl thio group Chemical group 0.000 claims description 4
- 125000005100 aryl amino carbonyl group Chemical group 0.000 claims description 4
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 4
- 125000005110 aryl thio group Chemical group 0.000 claims description 4
- 125000004104 aryloxy group Chemical group 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000004473 dialkylaminocarbonyl group Chemical group 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 3
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 3
- BMKDZUISNHGIBY-ZETCQYMHSA-N (+)-dexrazoxane Chemical compound C([C@H](C)N1CC(=O)NC(=O)C1)N1CC(=O)NC(=O)C1 BMKDZUISNHGIBY-ZETCQYMHSA-N 0.000 claims description 2
- 102100025573 1-alkyl-2-acetylglycerophosphocholine esterase Human genes 0.000 claims description 2
- VSNHCAURESNICA-NJFSPNSNSA-N 1-oxidanylurea Chemical compound N[14C](=O)NO VSNHCAURESNICA-NJFSPNSNSA-N 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- 108010024976 Asparaginase Proteins 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- AXDLCFOOGCNDST-UHFFFAOYSA-N N-methyl-DL-tyrosine Natural products CNC(C(O)=O)CC1=CC=C(O)C=C1 AXDLCFOOGCNDST-UHFFFAOYSA-N 0.000 claims description 2
- 101710183280 Topoisomerase Proteins 0.000 claims description 2
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 2
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 2
- 229940100198 alkylating agent Drugs 0.000 claims description 2
- 239000002168 alkylating agent Substances 0.000 claims description 2
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 claims description 2
- JKOQGQFVAUAYPM-UHFFFAOYSA-N amifostine Chemical compound NCCCNCCSP(O)(O)=O JKOQGQFVAUAYPM-UHFFFAOYSA-N 0.000 claims description 2
- 229960001097 amifostine Drugs 0.000 claims description 2
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 2
- 230000001548 androgenic effect Effects 0.000 claims description 2
- 229940045799 anthracyclines and related substance Drugs 0.000 claims description 2
- 229940044684 anti-microtubule agent Drugs 0.000 claims description 2
- 125000004658 aryl carbonyl amino group Chemical group 0.000 claims description 2
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 2
- 230000003115 biocidal effect Effects 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- UHDGCWIWMRVCDJ-ZAKLUEHWSA-N cytidine Chemical class O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-ZAKLUEHWSA-N 0.000 claims description 2
- 229960000605 dexrazoxane Drugs 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 150000005699 fluoropyrimidines Chemical class 0.000 claims description 2
- 229940022353 herceptin Drugs 0.000 claims description 2
- 239000005556 hormone Substances 0.000 claims description 2
- 229940088597 hormone Drugs 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- 229960004768 irinotecan Drugs 0.000 claims description 2
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 claims description 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 2
- 229940127557 pharmaceutical product Drugs 0.000 claims description 2
- 230000005855 radiation Effects 0.000 claims description 2
- 229930002330 retinoic acid Natural products 0.000 claims description 2
- 229960005314 suramin Drugs 0.000 claims description 2
- FIAFUQMPZJWCLV-UHFFFAOYSA-N suramin Chemical compound OS(=O)(=O)C1=CC(S(O)(=O)=O)=C2C(NC(=O)C3=CC=C(C(=C3)NC(=O)C=3C=C(NC(=O)NC=4C=C(C=CC=4)C(=O)NC=4C(=CC=C(C=4)C(=O)NC=4C5=C(C=C(C=C5C(=CC=4)S(O)(=O)=O)S(O)(=O)=O)S(O)(=O)=O)C)C=CC=3)C)=CC=C(S(O)(=O)=O)C2=C1 FIAFUQMPZJWCLV-UHFFFAOYSA-N 0.000 claims description 2
- 229960000303 topotecan Drugs 0.000 claims description 2
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 claims description 2
- 229960001727 tretinoin Drugs 0.000 claims description 2
- 230000001093 anti-cancer Effects 0.000 claims 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 2
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 claims 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-O hydron;quinoline Chemical compound [NH+]1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-O 0.000 claims 2
- 150000003838 adenosines Chemical class 0.000 claims 1
- 125000005265 dialkylamine group Chemical group 0.000 claims 1
- 230000001076 estrogenic effect Effects 0.000 claims 1
- 150000003057 platinum Chemical class 0.000 claims 1
- 210000003411 telomere Anatomy 0.000 claims 1
- 102000055501 telomere Human genes 0.000 claims 1
- 108091035539 telomere Proteins 0.000 claims 1
- 125000003396 thiol group Chemical class [H]S* 0.000 claims 1
- 210000004027 cell Anatomy 0.000 description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 239000000047 product Substances 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- 238000006243 chemical reaction Methods 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 108091034117 Oligonucleotide Proteins 0.000 description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- 230000014759 maintenance of location Effects 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 4
- 101100184046 Schizosaccharomyces pombe (strain 972 / ATCC 24843) mid1 gene Proteins 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 4
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- WCKQPPQRFNHPRJ-UHFFFAOYSA-N 4-[[4-(dimethylamino)phenyl]diazenyl]benzoic acid Chemical compound C1=CC(N(C)C)=CC=C1N=NC1=CC=C(C(O)=O)C=C1 WCKQPPQRFNHPRJ-UHFFFAOYSA-N 0.000 description 3
- 108020004414 DNA Proteins 0.000 description 3
- 102000053602 DNA Human genes 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 3
- 229930182816 L-glutamine Natural products 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229930182555 Penicillin Natural products 0.000 description 3
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 230000008033 biological extinction Effects 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- 230000002255 enzymatic effect Effects 0.000 description 3
- 230000005284 excitation Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000012894 fetal calf serum Substances 0.000 description 3
- 238000007429 general method Methods 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 229940049954 penicillin Drugs 0.000 description 3
- 239000003880 polar aprotic solvent Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 3
- 150000003254 radicals Chemical group 0.000 description 3
- 239000012429 reaction media Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 230000000087 stabilizing effect Effects 0.000 description 3
- 229960005322 streptomycin Drugs 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- XKDPIURMGBVXAB-UHFFFAOYSA-N 2-methylquinoline-4,6-diamine Chemical compound C1=C(N)C=CC2=NC(C)=CC(N)=C21 XKDPIURMGBVXAB-UHFFFAOYSA-N 0.000 description 2
- IXLVUUFUDRJUSL-RPBOFIJWSA-N 5-[[4-(3-acetamidophenyl)phenyl]methyl]-n-[(1s,2r)-2-phenylcyclopropyl]-1,3-oxazole-4-carboxamide Chemical compound CC(=O)NC1=CC=CC(C=2C=CC(CC3=C(N=CO3)C(=O)N[C@@H]3[C@H](C3)C=3C=CC=CC=3)=CC=2)=C1 IXLVUUFUDRJUSL-RPBOFIJWSA-N 0.000 description 2
- TZGKBJFLOXXKNK-UHFFFAOYSA-N 6-n-(4-amino-6-methylsulfanyl-1,3,5-triazin-2-yl)-2-methylquinoline-4,6-diamine Chemical class CSC1=NC(N)=NC(NC=2C=C3C(N)=CC(C)=NC3=CC=2)=N1 TZGKBJFLOXXKNK-UHFFFAOYSA-N 0.000 description 2
- SRNYYVYADVGFRC-UHFFFAOYSA-N 6-n-[4-chloro-6-(diethylamino)-1,3,5-triazin-2-yl]-2-methylquinoline-4,6-diamine Chemical compound CCN(CC)C1=NC(Cl)=NC(NC=2C=C3C(N)=CC(C)=NC3=CC=2)=N1 SRNYYVYADVGFRC-UHFFFAOYSA-N 0.000 description 2
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 2
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- DZBUGLKDJFMEHC-UHFFFAOYSA-N acridine Chemical compound C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 description 2
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 239000007978 cacodylate buffer Substances 0.000 description 2
- 230000032823 cell division Effects 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 229960000684 cytarabine Drugs 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- 238000001962 electrophoresis Methods 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 235000009518 sodium iodide Nutrition 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000007790 solid phase Substances 0.000 description 2
- 238000002798 spectrophotometry method Methods 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 description 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- LRMDXTVKVHKWEK-UHFFFAOYSA-N 1,2-diaminoanthracene-9,10-dione Chemical class C1=CC=C2C(=O)C3=C(N)C(N)=CC=C3C(=O)C2=C1 LRMDXTVKVHKWEK-UHFFFAOYSA-N 0.000 description 1
- JIHQDMXYYFUGFV-UHFFFAOYSA-N 1,3,5-triazine Chemical class C1=NC=NC=N1 JIHQDMXYYFUGFV-UHFFFAOYSA-N 0.000 description 1
- TZMSYXZUNZXBOL-UHFFFAOYSA-N 10H-phenoxazine Chemical compound C1=CC=C2NC3=CC=CC=C3OC2=C1 TZMSYXZUNZXBOL-UHFFFAOYSA-N 0.000 description 1
- SSKRDBGUCUIWTE-UHFFFAOYSA-N 2,4-dichloro-4-methylsulfanyl-1h-1,3,5-triazine Chemical compound CSC1(Cl)NC(Cl)=NC=N1 SSKRDBGUCUIWTE-UHFFFAOYSA-N 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- OSBLTNPMIGYQGY-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;2-[2-[bis(carboxymethyl)amino]ethyl-(carboxymethyl)amino]acetic acid;boric acid Chemical compound OB(O)O.OCC(N)(CO)CO.OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O OSBLTNPMIGYQGY-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- UJVBZCCNLAAMOV-UHFFFAOYSA-N 2h-1,2-benzothiazine Chemical compound C1=CC=C2C=CNSC2=C1 UJVBZCCNLAAMOV-UHFFFAOYSA-N 0.000 description 1
- CMLFRMDBDNHMRA-UHFFFAOYSA-N 2h-1,2-benzoxazine Chemical compound C1=CC=C2C=CNOC2=C1 CMLFRMDBDNHMRA-UHFFFAOYSA-N 0.000 description 1
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 1
- UMCMPZBLKLEWAF-BCTGSCMUSA-N 3-[(3-cholamidopropyl)dimethylammonio]propane-1-sulfonate Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCC[N+](C)(C)CCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 UMCMPZBLKLEWAF-BCTGSCMUSA-N 0.000 description 1
- 229940105325 3-dimethylaminopropylamine Drugs 0.000 description 1
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 1
- HYWCPNMPNFJCMD-UHFFFAOYSA-N 4,6-dichloro-n,n-diethyl-1,3,5-triazin-2-amine Chemical compound CCN(CC)C1=NC(Cl)=NC(Cl)=N1 HYWCPNMPNFJCMD-UHFFFAOYSA-N 0.000 description 1
- FQYRLEXKXQRZDH-UHFFFAOYSA-N 4-aminoquinoline Chemical compound C1=CC=C2C(N)=CC=NC2=C1 FQYRLEXKXQRZDH-UHFFFAOYSA-N 0.000 description 1
- UBJFKOPTJCCYKD-UHFFFAOYSA-N 6-n-(4-chloro-6-methylsulfanyl-1,3,5-triazin-2-yl)-2-methylquinoline-4,6-diamine Chemical compound CSC1=NC(Cl)=NC(NC=2C=C3C(N)=CC(C)=NC3=CC=2)=N1 UBJFKOPTJCCYKD-UHFFFAOYSA-N 0.000 description 1
- UJZHAGVXRGISLB-UHFFFAOYSA-N 6-n-(6-chloro-4-methylsulfanyl-1h-triazin-2-yl)-2-methylquinoline-4,6-diamine Chemical compound N1C(Cl)=CC(SC)=NN1NC1=CC=C(N=C(C)C=C2N)C2=C1 UJZHAGVXRGISLB-UHFFFAOYSA-N 0.000 description 1
- CNCPCKWUSGUQRA-UHFFFAOYSA-N 6-n-[4-[2-(dimethylamino)ethylamino]-6-methylsulfanyl-1,3,5-triazin-2-yl]-2-methylquinoline-4,6-diamine Chemical compound CSC1=NC(NCCN(C)C)=NC(NC=2C=C3C(N)=CC(C)=NC3=CC=2)=N1 CNCPCKWUSGUQRA-UHFFFAOYSA-N 0.000 description 1
- ROPIDAPNTLRVRQ-UHFFFAOYSA-N 6-n-[6-chloro-4-(diethylamino)-1h-triazin-2-yl]-2-methylquinoline-4,6-diamine Chemical compound N1C(Cl)=CC(N(CC)CC)=NN1NC1=CC=C(N=C(C)C=C2N)C2=C1 ROPIDAPNTLRVRQ-UHFFFAOYSA-N 0.000 description 1
- VVIAGPKUTFNRDU-UHFFFAOYSA-N 6S-folinic acid Natural products C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-UHFFFAOYSA-N 0.000 description 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- 238000009010 Bradford assay Methods 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- FVLVBPDQNARYJU-XAHDHGMMSA-N C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O Chemical compound C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O FVLVBPDQNARYJU-XAHDHGMMSA-N 0.000 description 1
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 1
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- MPJKWIXIYCLVCU-UHFFFAOYSA-N Folinic acid Natural products NC1=NC2=C(N(C=O)C(CNc3ccc(cc3)C(=O)NC(CCC(=O)O)CC(=O)O)CN2)C(=O)N1 MPJKWIXIYCLVCU-UHFFFAOYSA-N 0.000 description 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 1
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- 238000012408 PCR amplification Methods 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 239000005662 Paraffin oil Substances 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- HFVNWDWLWUCIHC-GUPDPFMOSA-N Prednimustine Chemical compound O=C([C@@]1(O)CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)[C@@H](O)C[C@@]21C)COC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 HFVNWDWLWUCIHC-GUPDPFMOSA-N 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 239000008051 TBE buffer Substances 0.000 description 1
- 108010006785 Taq Polymerase Proteins 0.000 description 1
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 1
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 1
- IVTVGDXNLFLDRM-HNNXBMFYSA-N Tomudex Chemical compound C=1C=C2NC(C)=NC(=O)C2=CC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)S1 IVTVGDXNLFLDRM-HNNXBMFYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- SBPHTBRNCKOLCA-MCDZGGTQSA-N [C@@H]1([C@H](O)[C@H](O)[C@@H](CO)O1)N1C=NC=2C(N)=NC=NC12.N1C(N)=NC=2N=CNC2C1=S Chemical class [C@@H]1([C@H](O)[C@H](O)[C@@H](CO)O1)N1C=NC=2C(N)=NC=NC12.N1C(N)=NC=2N=CNC2C1=S SBPHTBRNCKOLCA-MCDZGGTQSA-N 0.000 description 1
- PZXAQCDMGOGLKE-UHFFFAOYSA-N [Pt].CN(C)c1nc(nc(n1)N(C)C)N(C)C Chemical class [Pt].CN(C)c1nc(nc(n1)N(C)C)N(C)C PZXAQCDMGOGLKE-UHFFFAOYSA-N 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- XCPGHVQEEXUHNC-UHFFFAOYSA-N amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 description 1
- 229960001220 amsacrine Drugs 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- 159000000009 barium salts Chemical class 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- UDSAIICHUKSCKT-UHFFFAOYSA-N bromophenol blue Chemical compound C1=C(Br)C(O)=C(Br)C=C1C1(C=2C=C(Br)C(O)=C(Br)C=2)C2=CC=CC=C2S(=O)(=O)O1 UDSAIICHUKSCKT-UHFFFAOYSA-N 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- 229910052792 caesium Inorganic materials 0.000 description 1
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229960004630 chlorambucil Drugs 0.000 description 1
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 239000008139 complexing agent Substances 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- RGWHQCVHVJXOKC-SHYZEUOFSA-J dCTP(4-) Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)C1 RGWHQCVHVJXOKC-SHYZEUOFSA-J 0.000 description 1
- 229960000640 dactinomycin Drugs 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- IUNMPGNGSSIWFP-UHFFFAOYSA-N dimethylaminopropylamine Chemical compound CN(C)CCCN IUNMPGNGSSIWFP-UHFFFAOYSA-N 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 239000012154 double-distilled water Substances 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000000295 emission spectrum Methods 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 229960001904 epirubicin Drugs 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 238000000695 excitation spectrum Methods 0.000 description 1
- 229960000961 floxuridine Drugs 0.000 description 1
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 1
- 229960005304 fludarabine phosphate Drugs 0.000 description 1
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- VVIAGPKUTFNRDU-ABLWVSNPSA-N folinic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-ABLWVSNPSA-N 0.000 description 1
- 235000008191 folinic acid Nutrition 0.000 description 1
- 239000011672 folinic acid Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 229960000908 idarubicin Drugs 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960001691 leucovorin Drugs 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000012160 loading buffer Substances 0.000 description 1
- 229960002247 lomustine Drugs 0.000 description 1
- 229950008745 losoxantrone Drugs 0.000 description 1
- YROQEQPFUCPDCP-UHFFFAOYSA-N losoxantrone Chemical compound OCCNCCN1N=C2C3=CC=CC(O)=C3C(=O)C3=C2C1=CC=C3NCCNCCO YROQEQPFUCPDCP-UHFFFAOYSA-N 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 229960001156 mitoxantrone Drugs 0.000 description 1
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 1
- DILRJUIACXKSQE-UHFFFAOYSA-N n',n'-dimethylethane-1,2-diamine Chemical compound CN(C)CCN DILRJUIACXKSQE-UHFFFAOYSA-N 0.000 description 1
- 230000017066 negative regulation of growth Effects 0.000 description 1
- PGSADBUBUOPOJS-UHFFFAOYSA-N neutral red Chemical compound Cl.C1=C(C)C(N)=CC2=NC3=CC(N(C)C)=CC=C3N=C21 PGSADBUBUOPOJS-UHFFFAOYSA-N 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229940127084 other anti-cancer agent Drugs 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 229960002340 pentostatin Drugs 0.000 description 1
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 1
- 125000002080 perylenyl group Chemical group C1(=CC=C2C=CC=C3C4=CC=CC5=CC=CC(C1=C23)=C45)* 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229960004694 prednimustine Drugs 0.000 description 1
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
- 229960000624 procarbazine Drugs 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 229960004432 raltitrexed Drugs 0.000 description 1
- 239000013074 reference sample Substances 0.000 description 1
- 108091035233 repetitive DNA sequence Proteins 0.000 description 1
- 102000053632 repetitive DNA sequence Human genes 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 229960003440 semustine Drugs 0.000 description 1
- 230000009758 senescence Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012475 sodium chloride buffer Substances 0.000 description 1
- IHQKEDIOMGYHEB-UHFFFAOYSA-M sodium dimethylarsinate Chemical compound [Na+].C[As](C)([O-])=O IHQKEDIOMGYHEB-UHFFFAOYSA-M 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 210000001082 somatic cell Anatomy 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 229960004964 temozolomide Drugs 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- NLIVDORGVGAOOJ-MAHBNPEESA-M xylene cyanol Chemical compound [Na+].C1=C(C)C(NCC)=CC=C1C(\C=1C(=CC(OS([O-])=O)=CC=1)OS([O-])=O)=C\1C=C(C)\C(=[NH+]/CC)\C=C/1 NLIVDORGVGAOOJ-MAHBNPEESA-M 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
1 CHEMICAL DERIVATIVES AND THEIR APPLICATION AS ANTITELOMERASE AGENT The present invention relates to cancer therapy and to novel anticancer agents having a mechanism of action which is quite specific. It also relates to novel chemical compounds as well as their therapeutic application in humans.
The present invention relates to the use of novel nonnucleotide chemical compounds which interact with specific structures of deoxyribonucleic acid (DNA). These novel compounds consist of a distribution agent linked to an aminoaromatic group. These novel compounds are useful in the treatment of cancers and act in particular as telomerase-inhibiting agents. They are particularly useful for stabilizing DNA in G-quadruplex structure (guanine tetrads). The therapeutic application of the inhibition of telomerase via the stabilization of these G-quadruplexes is the termination of cellular mitosis and the death of rapidly-dividing cells such as cancer cells and possibly the induction of the senescence of cancer cells.
The compounds of the present invention have the advantage, from the therapeutic point of view, of blocking telomerase. From a biological point of view, telomerase allows the addition of repetitive DNA sequences of the T T A G G G type, termed telomeric sequences, at the end of the telomer, during cell division. Through this action, telomerase renders the cell immortal. Indeed, in the absence of this enzymatic activity, the cell loses, at each division, 100 to 150 bases, which rapidly renders it senescent. During the appearance of rapidly-dividing cancer cells, it appeared that these cells possessed telomers which were maintained at a stable length during cell division. In these cancer cells, it appeared that telomerase was highly activated and that it allowed the addition of repetitive motifs of telomeric sequences at the end of the telomer and therefore allowed conservation of the length of the telomer in the cancer cells. It appeared during the past few years that more than 85% of cancer cells showed positive tests for the presence of telomerase whereas somatic cells do not show this characteristic.
Thus, telomerase is a highly coveted target for treating cancer cells. The first obvious approach for blocking telomerase was the use of nucleotide structures (Chen et al., Proc. Natl. Acad. Sci. USA 93(7), 2635-2639). Among the nonnucleotide compounds which have been used in the prior art, there may be mentioned the diaminoanthraquinones (Sun et al., J.
Med. Chem. 40(14), 2113-6) or the diethyloxadicarbocyanins (Wheelhouse R.T. et al., J. Am. Chem. Soc.
1998(120) 3261-2).
27-Feb-2008 13:06 Watermark +61298887600 15/26 00 3 0 SPatent WO 99/40087 describes the use of compounds which interact with .C the G-quadruplex structures which are perylene compounds and carbocyanins containing at least seven rings including two heterocycles.
It appeared, quite surprisingly, that simple structures made it possible to obtain a result which is at least equivalent with structures which are a lot less complicated from a chemical point of view. The compounds of the present 00 invention which meet the intended objective, that is to say which bind the Gquadruplex structure and thereby exhibit a telomerase-inhibiting activity, ccorrespond to the following general formula: O 10 nitrogen-containing aromatic ring NR3 distribution agent NR' 3 nonaromatic Cl hydrocarbon chain, nonaromatic hydrocarbon chain being selected from a linear or branched alkyl (CI-C 4 a linear or branched alkenyl (C 2
-C
4 chain, a cycloalkyl (C3-.C 18 chain, a cycloalkenyl (C3-C18) chain and a heterocycloalkyl (C 3 -C1a) chain which optionally includes the nitrogen atom, wherein 1) the nitrogen-containing aromatic ring represents: a) a quinoline optionally substituted with at least i) a group N(Ra)(Rb) in which Ra and Rb, which are identical or different, represent hydrogen or a C1-C 4 alkyl radical or ii) a group ORa in which Ra is as defined above b) a quinoline possessing a nitrogen atom in quaternary form optionally substituted with a group selected from: 4-amino-, 4-methylamino- and 4-dimethylamino-, attached at the 4 position or c) a benzamidine or d) a pyridine, attached at the 4 position, 2) R 3 and R' 3 which are identical or different, represent independently of each other, hydrogen or a C1-C4 alkyl radical 3) the distribution agent represents: a triazine group, a triazine group substituted with i) a alkyl radical having 1 to 4 carbon atoms, ii) a thiol radical, iii) an hydroxy radical, or iv) an amino radical, COMS ID No: ARCS-180904 Received by IP Australia: Time 13:18 Date 2008-02-27 27-Feb-2008 13:07 Watermark +61298887600 16/26 00 4 0 0 v) wherein the thiol, hydroxy or amino radicals are unsubstituted or .0 substituted with one or more short-chain alkyl groups containing 1 to
C)
[L 4 carbon atoms and wherein the alkyl is unsubstituted or substituted with a halogen atom or a salt thereof; wherein the nonaromatic hydrocarbon chain is optionally substituted with one or more atoms or radicals chosen from halogen atoms, hydroxyl, aryl, heteroaryl, Salkyloxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, C dialkylamino, diarylamino, amidino, guanidine, alkylcarbonylamino, o 10 arylcarbonylamino, carboxyl, alkyloxycarbonyl or aryloxycarbonyl, aminocarbonyl, l alkylaminocarbonyl, arylaminocarbonyl, dialkylaminocarbonyl, alkycarbonyl arylcarbonyl, cyano and trifluoromethyl.
The alkyl chains of the optional substituents of the hydrocarbon chain preferably contain 1 to 4 carbon atoms and the aryl groups of the optional substituents of the hydrocarbon chain preferably contain 5 to 18 carbon atoms.
COMS ID No: ARCS-180904 Received by IP Australia: Time 13:18 Date 2008-02-27 PAGES 5 TO 7 HAVE BEEN LEFT BLANK INTENTIONALLY 8 It is evident that the quinoline motifs may be substituted by any other group not involved in the intended application; thus, acridine or isoquinoline or quinazoline or quinoxaline or phthalazine or benzothiazine or benzoxazine or phenoxazine or phenothiazine groups are included in the definition of the quinoline groups.
Among the above compounds of formula there are preferred those comprising a heterocycle chosen from the 4-aminoquinolyl, 4-alkyl- or 4-dialkylaminoquinolyl, 4-aminoquinolinium or quinolinium groups in which the quinolinium ring is optionally substituted with a methyl group.
As regards the groups A, they preferably represent the methylthio, amino, alkylamino or dialkylamino radical, in which radicals the alkyl groups possess 1 to 4 carbon atoms.
As regards the nonaromatic hydrocarbon chain, it preferably represents a 2-(dialkylamino)ethyl, 3-(dialkylamino)propyl, 2-(N-alkyl-N-arylamino)ethyl or 3-(N-alkyl-N-arylamino)propyl chain in which the alkyl groups preferably contain 1 to 4 carbon atoms, or more preferably still 1 to 2 carbon atoms and the aryl groups preferably contain 5 to 18 carbon atoms, more preferably still 6 carbon atoms.
Another subject of the present invention relates to the compounds of formula as novel 27-Feb-2008 13:07 Watermark +61298887600 17/26 00 9 0 Schemical products. It therefore relates to the novel products corresponding to the .C following formula
A
C N N RN N NR' 3 Ar, Alk 00 in which: C 5 1) A represents o a) an amino group of formula NRIR2, in which R1 and R2, which are 0 identical or different, represent hydrogen or a straight or branched alkyl group containing 1 to 4 carbon atoms or b) a group OR1 or SR1 in which R1 has the same meaning as above or c) an alky] group containing 1 to 4 carbon atoms or a trifluoromethyl group or d) a hydrogen atom or e) a halogen atom chosen from fluorine, chlorine, bromine and iodine 2) R3 and R'3, which are identical or different, represent independently of each other hydrogen or a C1-C4 alkyl group 3) Arl represents a nitrogen-containing aromatic ring representing: a) a quinoline optionally substituted with at least i) a group N(Ra)(Rb) in which Ra and Rb, which are identical or different, represent hydrogen or a C1-C4 alkyl radical or ii) a group ORa in which Ra is as defined above b) a quinoline possessing a nitrogen atom in quaternary form optionally substituted with a group selected from: 4-amino-, 4-methylamino- and 4-dimethylamino-, attached at the 4 position or c) a benzamidine or d) a pyridine attached at the 4-position or fused with an aryl or heteroaryl group optionally substituted with a C1-C4 alkyl group 4) Alk represents a nonaromatic, optionally substituted, hydrocarbon chain as hereinbefore defined, chosen from alkyl (C1-C4), alkenyl (C2-C4), wherein the alkyl and alkenyl chain are linear or branched, cycloalkyl (C3-C18), COMS ID No: ARCS-180904 Received by IP Australia: Time 13:18 Date 2008-02-27 27-Feb-2008 13:08 Watermark +61298887600 18/26 00 0 cycloalkenyl (C3-C18), heterocycloalkyl (C3-C18), and heterocycloalkyl (C3- CC18) including the nitrogen atom of the NR'3 group
C)
(1)or a salt thereof; wherein the nonaromatic hydrocarbon chain is optionally substituted with one or more atoms or radicals chosen from halogen atoms, hydroxyl, aryl, heteroaryl, alkyloxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino andlor 00 arylamino, dialkylamino, diarylamino, amidino, guanidine, alkylcarbonlamino, arylcarbonlamino, carboxyl, alkyloxycarbonyl, aryloxycarbonyl, aminocarbonyl, N alkylaminocarbonyl, arylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonyl, o 10 arycarbonyl, cyano and trifluoromethyl.
0 Ci The preferred compounds of formula are those for which AR 1 represents a group chosen from the COMS ID No: ARCS-180904 Received by IP Australia: Time 13:18 Date 2008-02-27 11 following units: 4-amino- or 4-methylamino- or 4dimethylaminoquinolyl or quinolynium whose quinolinium nucleus is optionally substituted with a methyl group.
The preferred compounds of general formula are those for which A represents an amino or dimethylamino or more preferably methylthio group.
The compounds of general formula which are preferred are those for which the nonaromatic hydrocarbon chain represents a 2-(dialkylamino)ethyl, 3-(dialkylamino)propyl, 2-(N-alkyl-N-arylamino)ethyl or 3-(N-alkyl-N-arylamino)propyl chain in which the alkyl groups contain 1 to 4 carbon atoms, in particular 1 to 2 carbon atoms and the aryl groups contain 5 to 18 carbon atoms, in particular 6 carbon atoms.
The compounds of general formula for which the nonaromatic hydrocarbon chain represents a 2-(N-alkyl-N-arylamino)ethyl chain such as the 2-(N-m.tolyl-N-ethylamino)ethyl chain are most particularly preferred.
Another subject of the present invention relates to the use of the compounds of formula as pharmaceutical product for human use.
The methods of preparing the compounds of formula (I)
A
N" N Ar I Alk NR N
NR'
3
(I)
are described below.
In the case where Arl and Alk are present, the triazine of general formula (A),may be obtained by sequential displacement of the halogen atoms, most generally of chlorine atoms, from the products of general formula by the amines Arl and then Alk of general formula according to scheme 1: R
R
NI rNN N X N N II 1- X N X R 3 NR N X X =Cl (or F or Br or I)
(D)
Alk-NH (C)
R'
3
R
N Alk
NR
3 N NR'
(A)
Scheme 1 Generally, the procedure is carried out with 1 mole of dihalo-s-triazine, or trihalo-s-triazine, and 1 mole of amine Arl. The procedure is preferably carried out in an inert solvent such as acetone which is optionally aqueous or an alcohol which is optionally aqueous, such as ethanol, or a halogenated solvent such as dichloromethane, or an ether such as diethyl ether or dioxane, or a polar aprotic solvent such as DMF, DMSO or NMP. According to a better way of carrying out the invention, the procedure is carried out at a temperature of between 20 0 C and 50°C. Next, 1 mole of 13 amine Alk is added to the product of general formula which may be optionally isolated. The procedure is carried out in particular at a temperature of between 0 C and the reflux temperature.
Advantageously, it is possible to carry out the procedure under the conditions described in J.
Fluor. Chem., 1988, 39(1), 117-123.
General method 2 According to a second method, the products of general formula in which Ar are as defined above and R represents a group NR1R2 or OR1 or SR1 may also be prepared by nucleophilic displacement of a halogen atom, generally a chlorine atom, from a product of general formula in which R represents a halogen atom according to scheme 2:
R
N N RR 2 NH or RO- or R 1
S-
Ar N /A kAlk SNR NR ArA N N /N A lk
NR
3 N NRNR' N NR
(A)
R CI (or F or Br or I) R= NRR 2 or OR 1 or SR, Scheme 2 The procedure is generally carried out by condensing 1 mole of product of general formula in which R represents a halogen atom, preferably a chlorine atom, with 1 mole of amine R1R2NH or alcoholate R10- or thioalcoholate R1S. The reaction 14 takes place in an inert medium under the reaction conditions. There may be mentioned among the inert solvents acetone which is optionally aqueous or an alcohol which is optionally aqueous such as ethanol, or a halogenated solvent such as dichloromethane, or an ether such as diethyl ether or dioxane, or a polar aprotic solvent such as DMF, DMSO or NMP. When the entering group represents a group R1R2NH, the procedure is preferably carried out at a temperature of between 20 0 C and the reflux temperature, in the presence in particular of an organic base such as triethylamine, or an inorganic base such as sodium hydroxide or sodium or potassium carbonate. It is also possible not to use a base during the amination reaction, and to isolate a hydrochloride of the product of general formula the base of which can then be released. When the entering group represents a group R10- or R1S-, the procedure is preferably carried out with an alkali metal or alkaline-earth metal alcoholate or thioalcoholate, such as a sodium or potassium or lithium or ammonium or cesium or barium salt, in a polar aprotic solvent such as DMF or DMSO or NMP, at a temperature of between 50 0 C and the reflux temperature.
General method 3 According to a third method of preparing the compounds for which R represents a hydrogen atom or a straight or branched alkyl group containing from 1 to 4 carbon atoms, may also be prepared by condensation of a bisguanide of general formula with an acid derivative, preferably an acid chloride or a methyl ester of general formula according to scheme 3: 0
R
NH NH R CI Ar N Alk or N N Ak NRN N NR'\ Alk H Aro0 1
NR
3 N NR' 3 R O
(A)
Scheme 3 The condensation between the bisguanide of general formula and the acid derivative of general formula is generally carried out in an alcohol such as methanol or ethanol. The procedure is preferably carried out at a temperature of between 0°C and the reflux temperature.
The symmetric or asymmetric bisguanides of general formula may be obtained by carrying out the procedure under the conditions described in the literature and in particular according to Patent J.P. 94-4993.
General method 4 It is understood that the s-triazines of general formula may be obtained in the form of libraries, by applying the methods described in schemes 1, 2, 3 in parallel and/or combinatorial chemistry in liquid phase or in solid phase, it being understood that when the work is carried out in solid phase, any 16 one of the reagents is attached beforehand onto a solid support, chosen according to the chemical reaction involved, and that said chemical reaction is followed by an operation of cleaving the product of the reaction from the solid support.
The present invention also relates to therapeutic compositions containing a compound according to the invention, in combination with a pharmaceutically acceptable carrier according to the mode of administration chosen. The pharmaceutical composition may be provided in solid, liquid or liposome form.
Among the solid compositions, there may be mentioned powders, gelatin capsules, tablets. Among the oral forms, it is also possible to include the solid forms which are protected from the acidic medium of the stomach. The carriers used for the solid forms consist in particular of inorganic carriers such as phosphates, carbonates or organic carriers such as lactose, celluloses, starch or polymers. The liquid forms consist of solutions, suspensions or dispersions. They contain, as dispersive carrier, either water or an organic solvent (ethanol, NMP and the like) or mixtures of surfactants and solvents or of complexing agents and solvents.
The administered dose of the compounds of the invention will be adjusted by the practitioner 17 according to the route of administration to the patient and the condition of the latter.
The compounds of the present invention may be administered alone or mixed with other anticancer agents. Among the possible combinations, there may be mentioned alkylating agents and in particular cyclophosphamide, melphalan, ifosfamide, chlorambucil, busulfan, thiotepa, prednimustine, carmustine, lomustine, semustine, steptozotocin, decarbazine, temozolomide, procarbazine and hexamethylmelamine platinum derivatives such as in particular cisplatin, carboplatin or oxaliplatin antibiotic agents such as in particular bleomycin, mitomycin, dactinomycin, antimicrotubule agents such as in particular vinblastine, vincristine, vindesine, vinorelbine, taxoids (paclitaxel and docetaxel) anthracyclines such as in particular doxorubicin, daunorubicin, idarubicin, epirubicin, mitoxantrone, losoxantrone 18 group I and II topoisomerases such as etoposide, teniposide, amsacrine, irinotecan, topotecan and tomudex, fluoropyrimidines such as 5-fluorouracil, UFT, floxuridine, cytidine analogs such as cytarabine, gemcitabine, 6-mercaptomurine, 6-thioguanine adenosine analogs such as pentostatin, cytarabine or fludarabine phosphate methotrexate and folinic acid enzymes and various compounds such as L-asparaginase, hydroxyurea, trans-retinoic acid, suramine, dexrazoxane, amifostine, herceptin as well as etrogenic and androgenic hormones.
It is also possible to combine a radiation treatment with the compounds of the present invention.
These treatments may be administered simultaneously, separately or sequentially. The treatment will be adapted to the patient to be treated by the practitioner.
The G-quadruplex stabilizing activity may be determined by a method using the formation of a complex with fluorescein of which the experimental protocol is described below.
Oligonucleotides All the oligonucleotides, modified or otherwise, were synthesized by Eurogentec SA, Seraing, Belgium. The oligonucleotide FAM DABCYL carries the catalog reference OL-0371-0802. It has the sequence: GGGTTAGGGTTAGGGTTAGGG corresponding to 3.5 repeats of the human telomeric motif (strand rich in The fluorescein is attached to the 5' end, the DABCYL to the 3' end, by the chemical arms described by Eurogentec. The concentration of the samples is checked by spectrophotometry, recording the absorbance spectrum between 220 and 700 nm and using the molar extinction coefficient provided by the supplier.
Buffers All the experiments were carried out in a mM sodium cacodylate buffer pH 7.6 containing 0.1 M Lithium Chloride (or Sodium Chloride). The absence of fluorescent contamination in the buffer was checked beforehand. The fluorescent oligonucleotide is added at the final concentration of 0.2 pM.
Study of fluorescence All the measurements of fluorescence were carried out on a Spex Fluorolog DM1B apparatus, using an excitation line width of 1.8 nm and an emission line width of 4.5 nm. The samples are placed in a microquartz cuvette of 0.2 x 1 cm. The temperature of the sample is controlled by an external water bath. The oligonucleotide alone was analyzed at 20, 30, 40, 70 and 800C. The emission spectra are recorded using an excitation wavelength of 470 nm. The excitation spectra are recorded using either 515 nm or 588 nm as emission wavelength. The spectra are corrected for the response of the instrument by reference curves. A high extinction (80-90%) of the fluorescence of fluorescein at room temperature is observed, in agreement with an intramolecular folding of the oligonucleotide at 20 0 C in the form of a G-quadruplex, which induces juxtaposition of its 5' and 3' ends which are respectively linked to fluorescein and to DABCYL. This juxtaposition causes an alreadydescribed phenomenon of extinction of fluorescence which is used for "Molecular Beacons".
Fluorescence Tm: An oligonucleotide stock solution at the strand concentration of 0.2 gM in 0.1 M LiCI, 10 mM cacodylate buffer, pH 7.6, is prepared beforehand, heated briefly at 900C and slowly cooled to 20 0 C, and then distributed in aliquots of 600 il in the fluorescence cuvettes. 3 4~ of water (for the control) or 3 41 of test product (stock at 200 AM, final concentration 1 gM) are then added and mixed. The samples are then allowed to incubate for at least 1 hour at 200C before each measurement. The use of longer incubation times (up to 24 hours) has no influence on the result obtained.
21 Each experiment allows the measurement of only one sample. The latter is first incubated at an initial temperature of 200C, heated to 80 0 C over 38 minutes, left for 5 minutes at 800C and then cooled to 20 0 C over 62 minutes. During this time, the fluorescence is measured simultaneously at two emission wavelengths (515 nm and 588 nm) using 470 nm as excitation wavelength. A measurement is carried out every 30 seconds. The temperature of the water bath is recorded in parallel, and the fluorescence profile as a function of the temperature is reconstituted from these values. The fluorescence profiles are then normalized between 200C and 80 0 C, and the temperature for which the intensity of emission at 515 nm is the mean of those at high and low temperature is called Tm. Under these conditions, the Tm of the reference sample without addition of product is 440C in a Lithium Chloride buffer. This temperature is increased to more than 550C in a Sodium Chloride buffer. The addition of a G-quadruplex stabilizing compound induces an increase in the Tm. This increase is judged to be significant if it is greater than The antitelomerase biological activity is determined by the following experimental protocol: Preparation of the extract enriched in human telomerase activity The leukemia line HL60 is obtained from ATCC (American Type Culture Collection, Rockville USA). The 22 cells are cultured in suspension in RPMI 1640 medium containing L-Glutamine at 2 mM, Penicillin 200 U/ml, streptomycin 200 gg/ml, gentamycin 50 ig/ml and supplemented with 10% heat-inactivated fetal calf serum.
An aliquot of 105 cells is centrifuged at 3000xG and the supernatant discarded. The cell pellet is resuspended by several successive pipettings in 200 gi of lysis buffer containing 0.5% CHAPS, 10 mM Tris-HCl pH 7.5, 1 mM MgC1 2 1 mM EGTA, 5 mM P-mercaptoethanol, 0.1 mM PMSF and 10% glycerol and is stored in ice for 30 minutes. The lysate is centrifuged at 16 0000xG for 20 minutes at 4 0 C and 160 pl of supernatant is recovered. The proteins in the extract are assayed by the Bradford method. The extract is stored at -80 0
C.
Assay of the telomerase activity The inhibition of the telomerase activity is determined by a protocol for extension of the oligonucleotide TS 5
AATCGTTCGAGCAGAGTT
3 in the presence of a cellular extract enriched in telomerase activity and compounds which are added at various concentrations (10, 1, 0.1 and 0.01 ig/ml). The extension reaction is followed by a PCR amplification of the extension products with the aid of the oligonucleotides TS and CXext
GTGCCCTTACCCTTACCCTTACCCTAA
3 23 The reaction medium is prepared based on the following composition: Tris HC1 pH 8.3 20 mM MgC12 1.5 mM Tween 20 0.005% (W/V) EGTA 1 mM DATP 50 IM DGTP 50 AM DCTP 50 AM DTTP 50 ttM Oligonucleotide TS 2 pg/ml Oligonucleotide CXext 2 gg/ml Bovine serum albumin 0.1 mg/ml Taq DNA polymerase 1 U/ml alpha 32P dCTP (3000 0.5 l Ci/mmol) Telomerase extract 200 ng in a volume of 10 il Test product or solvent in a volume of 5 pl Double distilled water QS 50 tl The oligonucleotides are obtained from Eurogentec (Belgium) and are stored at -20 0 C at a stock concentration of 1 mg/ml in distilled water.
The reaction samples are assembled in 0.2 ml PCR tubes and one drop of paraffin oil is deposited on each of the reactions of the experiment before closing the tubes.
24 The reaction samples are then incubated in a Cetus 4800-type PCR apparatus under the following temperature conditions: minutes at 300C, 1 minute at 90 0
C,
followed by 30 cycle of, seconds at 940C, seconds at and 1 minute 30 seconds at 720C, followed by a final cycle of 2 minutes at 720C.
For each of the samples, an aliquot of 10 gl is pipetted under the oil layer and mixed with 5 tl of a loading buffer containing: TBE 3X glycerol 32% (W/V) Bromophenol blue 0.03% Xylene cyanol 0.03% The samples are then analyzed by electrophoresis on 12% acrylamide gel in a 1X TBE buffer for 1 hour at a voltage of 200 volts, with the aid of a Novex electrophoresis system.
The acrylamide gels are then dried on a sheet of whatmann 3MM paper at 800C for 1 hour.
The analysis and the quantification of the reaction products are carried out with the aid of an InstantImager apparatus (Pacard).
For each compound concentration tested, the results are expressed as percentage inhibition of the reaction and calculated from the untreated enzymatic control and from the enzyme-free sample (blank) according to the following formula: (Compound Value blank value/enzymatic control value blank value) x 100.
The concentration of compound inducing a inhibition of the telomerase reaction (IC50) is determined with the aid of a semilogarithmic graphical representation of the inhibition values obtained as a function of each of the compound concentrations tested.
A compound is considered to be active as an antitelomerase agent when the quantity inhibiting of the telomerase reaction is in particular less than gM.
The cytotoxic biological activity on human tumor lines is determined according to the following experimental protocol: The human cell lines KB and A549 are obtained from ATCC (American Type Culture Collection, Rockville USA). The A549 cells are cultured in a layer in a culture flask in RPMI 1640 medium containing L-Glutamine at 2 mM, Penicillin 200 U/ml, streptomycin 200 gg/ml and supplemented with 10% heat-inactivated fetal calf serum. The KB cells are cultured in a layer in a culture flask in Dulbelco's medium containing L-Glutamine at 2 mM, Penicillin 200 U/ml, streptomycin 200 gg/ml and supplemented with 10% heat-inactivated fetal calf serum.
26 The cells at the exponential growth phase are trypsinized, washed in IX PBS and are inoculated in 96-well microplates (Costar) in an amount of 4x10 4 cells/ml for A549 and of 1.5x10 4 cells/ml (0.2 ml/well) and then incubated for 96 hours in the presence of variable concentrations of product to be studied (10, 1, 0.1 and 0.01 gg/ml, each point in quadruplicate). 16 hours before the end of the incubation, 0.02% final of neutral red is added to each well. At the end of the incubation, the cells are washed with IX PBS and lysed with 1% sodium lauryl sulfate. The cellular incorporation of the dye, which reflects cellular growth, is evaluated by spectrophotometry at a wavelength of 540 nm for each sample with the aid of a Dynatech MR5000 reading apparatus.
For each compound concentration tested, the results are expressed as percentage inhibition of cellular growth and calculated from the untreated control and the culture medium free of cells (blank) according to the following formula: (Compound Value blank value/cell control value blank value) x 100.
The concentration of compound inducing a inhibition of growth (IC50) is determined with the aid of a semilogarithmic graphical representation of the inhibition values obtained as a function of each of the compound concentrations tested.
27 A compound is considered to be active as cytotoxic agent if the concentration inhibiting the growth of the tumor cells tested by 50% is in particular less than 10 gM.
The following and nonlimiting examples are given to illustrate the invention.
Example 1: Parallel synthesis of substituted derivatives of N6-[6-amino-4-methylsulfanyl-[1,3,5]triazin-2-yl]-2-methylquinoline-4,6-diamine
S-
N N
NH
2 SN N N -3
N
Preparation of N6-(6-chloro-4-methylsulfanyl- [1,3,5]triazin-2-yl)-2-methylquinoline-4,6-diamine 4.4 g (25 mmol) of 2-methylquinoline- 4,6-diamine, which may be prepared according to J. Med.
Chem. 1992, 35, 252, and 2.8 g (25 mmol) of sodium carbonate are successively added, in a 1 litre threenecked flask, to a solution of 5 g (25 mmol) of 2,6-dichloro-6-methylsulfanyl-[1,3,5]triazine, which may be prepared according to J. Amer. Chem. Soc., 1945, 67, 662, in 400 ml of tetrahydrofuran. The reaction mixture is heated under reflux for 16 hours. After evaporation of the tetrahydrofuran, the residue is 28 taken up in 400 ml of a mixture of water and dichloromethane (50-50 by volume). The organic phase is separated after settling out, dried over sodium sulfate and concentrated to dryness under reduced pressure.
7.5 g of N6-(6-chloro-4-methylsulfanyltriazin-2yl)-2-methylquinoline-4,6-diamine are then obtained, in the form of a pale yellow solid whose characteristics are the following: melting point 294 0
C
H NMR spectrum (300 MHz, (CD 3 2 SO d6, 6 in ppm) 2.43 3H); 2.52 3H); 6.47 1H); 6.61 (unresolved complex: 2H); 7.62 (broad d, J 9 Hz: 1H); 7.69 J 9 Hz: 1H); 8.32 (unresolved complex: 1H); 10.80 (unresolved complex: 1H).
Parallel synthesis of N6-[6-(2-dimethylaminoethylamino)-4-methylsulfanyl-[1,3,5]triazin-2-yl]- 2-methylquinoline-4,6-diamine (Example 1-1) mg (0.15 mmol) of N6-(6-amino-4-methylsulfanyl-[1,3,5]triazin-2-yl)-2-methylquinoline- 4,6-diamine are introduced into a heating magnetic reactor with a Zymark condenser, of the STEM RS2050 type, containing 25 wells in parallel each provided with a 50 ml glass tube. 5 ml of dioxane, 16 mg (0.15 mmol) of sodium carbonate, 23 mg (0.15 mmol) of sodium iodide and 27 mg (0.3 mmol) of 2-dimethylaminoethylamine are successively added to the first tube (Example The reaction medium is heated by reflux and under argon for 24 hours. After cooling, the 29 content of the tube is evaporated under reduced pressure, taken up in 5 ml of water and 5 ml of ethyl acetate and filtered. The organic phase is separated by settling out, dried and concentrated under reduced pressure. The crude product obtained is then purified by LC/MS using a Waters Xterra 3.5 gM C18 silica column 3 mm in diameter and 50 mm in length, eluting with a linear elution gradient consisting, at the starting time (to 0 min), of water containing 0.05% trifluoroacetic acid and, at the final time (tf 4 min), of acetonitrile containing 0.05% trifluoroacetic acid. 58 mg of N6-[(6-(methylquinolin- 6-ylamino)-4-methylthiotriazin-2-yl]quinaldine- 4,6-diamine trifluoroacetate are thus obtained, after purification, whose characteristics are the following: mass spectrum (DAD-TIC) 454 (MH retention time 2.69 min (the retention times are obtained on a hypersil C 18 5 pm column 50 mm diameter 4.6 mm trade mark Purity Elite, eluting with a mixture of solvents A (H20/TFA 0.05%) and B (ACN/TFA 0.05%) with a linear gradient ranging from 95% A/5% B (t 0 min) to 10% A/90% B at t 3.5 min, then step 2 min).
Examples 1-1 to 1-26 were obtained by carrying out the procedure as above in a Zymark STEM RS2050 reactor. The structures, the various operating conditions used and the characteristics of Examples 1-1 to 1-26 are summarized in the table below: Example StutReaction conditions Characteristics No. of Mass Retention Ak('-Solven Heating mmol Of MH* time amine (min) 11dioxane 17 h.i 00* 0.3 384 2.69 1-2 dioxane 17 h.1100' 0.3 410 2.91 1-3 dioxane 17 h./100* 0.15 411 2.86 HO- N trans racemic 1-4 Ndioxane 3d/100 0.45 422 2.85 3-RSj (Ndioxane 17 h./iCC' 0.15 396 2.84
N~N
M2-S
NH
1-6 dioxane 17 h.1100' 0.15 424 2.79 '-NH 2-RS 1-7 H2 N dioxane 17 h.1100 0.15 410 2.72 HN-' NH trans racemic 1-8 HN dioxane 2d./100* 0.3 452 2.81 H,N NH 1-9 /dioxanelO 24 h./100* 0.3 425 2.43 HN mI/DMF1 -NH 1-10 dioxanelO 24 h.1100* 0.3 410 2.51 HN Nml/DMF1 NH 1 1-11 -N N dioxanelO 24 h./1 DO. 0.3 424 2.50 mlDMF1 V12 N za 2: 0.3 398 24 dioxanelO 24 h.lDO 0.3 398 2.46 mlIDMF1 1-14 dioxanelO 24h./lD 0.3 412 2.47 mL'DMF1 1-15 H dioxanelO 24 h./100' 0.3 384 2.48 NN mIDMF1 NH 1-16H doaeD 24 hJ1100' 0.3 396 2.49 KN- NH -i/DMF1
MVMF
1.17 dioxanelO 24h.100* 0.3 511 2.38 mUDMF1 1-18 N dioxanelO 24 h./iC' 0.3 459 2.62 N N/ mUDMF1 1-19 dioxanelO 24 n.1100' 0.3 410 2.44 C N mlDMFI 1-20 dioxanelO 24 h.1100C 0.3 410 2.52 mVDMF1 1-21 dioxanelO 24 h.1100* 0.3 422 2.55 m11DMF1 C NH 3-S 1-22 H dioxanel0 24 h./100' 0.3 400 2.36 HO N '-eNh mLDMF1 1-23 H dioxanel1 24 h./100' 0.3 384 2.40 N2 mltDMF1 1-24 dioxanel0 24 h.1100' 0.3 440 2.58 N m V D M F 1 1-25 dioxanelO 24 h./1001 0.3 410 2.48 N- mVDMF1 1-26 dioxanel0 24 h.1100' 0.3 474 2.86 mI/DMF 1 i~s~NH Example 2: Parallel synthesis of substituted derivatives of NG-[6-amino-4-diethylamino-[1,3,5]triazin-2-yl]-2-methylquinoline-4, 6-diamine
N
N NN
NH
2 1-
H
K'3 33 Preparation of N6-(6-chloro-4-diethylamino- [1,3,5]triazin-2-yl)-2-methylquinoline-4,6-diamine 3.91 g (22.5 mmol) of 2-methylquinoline- 4,6-diamine, which may be prepared according to J. Med.
Chem. 1992, 35, 252, and 2.4 g (22.5 mmol) of sodium carbonate are successively added, in a 1 litre threenecked flask, to a solution of 5 g (22.5 mmol) of commercial 2,6-dichloro-4-diethylamino-[1,3,5]triazine in 300 ml of tetrahydrofuran. The reaction mixture is heated to reflux for 20 hours. After evaporation of the tetrahydrofuran, the residue is taken up in 400 ml of a mixture of water and dichloromethane (50-50 by volume).
The organic phase is separated after settling out, dried over sodium sulfate and concentrated to dryness under reduced pressure. 7.4 g of N6-(6-chloro-4diethylaminotriazin-2-yl)-2-methylquinoline-4,6-diamine are thus obtained in the form of a yellow solid whose characteristics are the following: melting point 120 0
C
H NMR spectrum (300 MHz, (CD 3 2 SO d6, 8 in ppm): 1.14 (mt: 6H); 2.42 3H); from 3.50 to 3.70 (mt: 4H); 6.47 (s and unresolved complex: 3H in total); 7.54 (broad d, J 9 Hz: 1H); 7.67 (dd, J 9 and 2 Hz: 1H); 8.27 (unresolved complex: 1H); 10.09 (unresolved complex: 1H).
Parallel synthesis of N6-[(6-(3-dimethylaminopropylamino)-4-diethylamino-[1,3,5]triazin-3-yl]-2-methylquinoline-4,6-diamine (Example 2-1) 34 mg (0.13 mmol) of N6-(6-chloro-4-diethylamino-[1,3,5]triazin-2-yl)-2-methylquinoline- 4,6-diamine are introduced into a heating magnetic reactor with a Zymark condenser, of the STEM RS2050 type, containing 25 wells in parallel each provided with a 50 ml glass tube. 5 ml of DMF, 19 mg (0.14 mmol) of potassium carbonate, 21 mg (0.14 mmol) of sodium iodide and 14 mg (0.14 mmol) of 3-dimethylaminopropylamine are successively added to the first tube (Example The reaction medium is heated at 1200C under argon for 16 hours. After cooling, the content of the tube is evaporated under reduced pressure and taken up in 5 ml of water, filtered and washed with diethyl ether. The crude product obtained is then purified by LC/MS using a Waters Xterra 3.5 gM C18 silica column 3 mm in diameter and 50 mm in length, eluting with a linear elution gradient consisting, at the starting time (to 0 min), of water containing 0.05% trifluoroacetic acid and, at the final time (tf 4 min), of acetonitrile containing 0.05% trifluoroacetic acid. 12 mg of N6-[(6-(3-dimethylaminopropylamino)-4-diethylamino-[1,3,5]triazin-2-yl]- 2-methylquinoline-4,6-diamine are thus obtained, after purification, whose characteristics are the following: mass spectrum (DAD-TIC) 423 (MH retention time 0.79 min (the retention times are obtained on a hypersil C 18 5 pm column 50 mm diameter 4.6 mm trade mark Purity Elite, eluting with a mixture of solvents A (H20/TFA 0.05%) and B (ACN/TFA 0.05%) with a linear gradient ranging from 95% A/5% B (t 0 min) to 10% A/90% B at t 3.5 min, then step 2 min).
Examples 2-1 to 2-2 were obtained by carrying out the procedure as above in a Zymark STEM RS2050 reactor. The structures, the various operating conditions used and the characteristics of Examples 2-1 to 2-2 are summarized in the table below: Example Structure Reaction conditions Characteristics AlkN(R'3)- No. of Mass Retention Solvent Heating mmol of MH' time amine (min) 2-1 DMF 16 h./120' 0.14 423 0.79 -,IN 2-2 DMF 16 h./120' 0.14 421 0.79 -N N 36 Table of biological results Example TRAP G-4 Cytotoxicity telomerase ATm A549 g.M 0 C IC50 M 1-1 0.79 6 1-2 0.5 5.6 1-3 4.4 3.1 1-4 0.1 5.6 1.6 2.8 1-6 1.36 1-7 0.47 1-8 0.98 1-9 1.64 7 1-10 0.94 7 1-11 1.1 1-12 3.1 1-13 1-14 3.2 1-15 4.6 1-16 1.29 1-17 1.6 1-19 1 1-20 3.1 1-21 0.7 1-22 1-23 3.8 1-24 1-25 1.5 1-26 0.86 33 3 2-1 0.90 7.9 2-2 5.4
Claims (3)
- 27-Feb-2008 13:09 Watermark +61298887600 19/26 00 38 0 0 THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS: 1. A compound which binds the G-quadruplex structure of a telomere, characterized in that it has the following general formula: nitrogen-containing aromatic ring NR 3 distribution agent NR' 3 nonaromatic hydrocarbon chain, nonaromatic hydrocarbon chain being selected from a linear 0 or branched alkyl (C1-C4), a linear or branched alkenyl (C2-C4) chain, a cycloalkyl (C3-Cio) chain, a cycloalkenyl (C3-C18) chain and a heterocycloalkyl (C 3 -C 8 a) chain Cl which optionally includes the nitrogen atom, O wherein 0 C 10 1) the nitrogen-containing aromatic ring represents: b) a quinoline optionally substituted with at least i) a group N(Ra)(Rb) in which Ra and Rb, which are identical or different, represent hydrogen or a Cl-C4 alkyl radical or ii) a group ORa in which Ra is as defined above c) a quinoline possessing a nitrogen atom in quaternary form optionally substituted with a group selected from: 4-amino-, 4-methylamino- and 4-dimethylamino-, attached at the 4 position or d) a benzamidine or e) a pyridine, attached at the 4 position, 2) R 3 and R' 3 which are identical or different, represent independently of each other, hydrogen or a C1-C4 alkyl radical 3) the distribution agent represents: a triazine group, a triazine group substituted with i. a alkyl radical having 1 to 4 carbon atoms, ii. a thiol radical, iii. an hydroxy radical, or iv. an amino radical, v. wherein the thiol, hydroxy or amino radicals are unsubstituted or substituted with one or more short-chain alkyl groups containing 1 to 4 carbon atoms and wherein the alkyl is unsubstituted or substituted with a halogen atom or a salt thereof; COMS ID No: ARCS-180904 Received by IP Australia: Time 13:18 Date 2008-02-27 27-Feb-2008 13:09 Watermark +61298887600 20/26 00 39 0 0 wherein the nonaromatic hydrocarbon chain is optionally substituted with one or .O more atoms or radicals chosen from halogen atoms, hydroxyl, aryl, heteroaryl, alkyloxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, dialkylamino, diarylamino, amidino, guanidine, alkylcarbonylamino, arylcarbonylamino, carboxyl, alkyloxycarbonyl or aryloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, dialkylaminocarbonyl, alkycarbonyl 0 arylcarbonyl, cyano and trifluoromethyl. S2. The compound according to claim 1, wherein the distribution agent is a Striazine group. 3. The compound according to claim 1, wherein the nonaromatic hydrocarbon chain is chosen from the following: i) alkyl (C1-C4), alkenyl (C2-C4), wherein the alkyl and alkenyl are linear or branched, ii) cycloalkyl (C3-C18) iii) cycloalkenyl (C3-C18) iv) heterocycloalkyl (C3-Cia) and v) heterocycloakyl (C3-Cia) including the nitrogen atom of the NR' 3 group. 4. A compound according to claim 1, wherein the alkyl chains of the optional substituents of the hydrocarbon chain contain 1 to 4 carbon atoms and the aryl groups of the optional substituents of the hydrocarbon chain contain 5 to 18 carbon atoms. A compound according to claim 3, wherein the alkyl chains contain 2 to 3 carbon atoms, and the heterocycloalkyl or cycloalkyl chains contain 5 to 7 carbon atoms. 6. A compound according to claim 1, wherein it corresponds to formula (I) below: COMS ID No: ARCS-180904 Received by IP Australia: Time 13:18 Date 2008-02-27 27-Feb-2008 13:10 Watermark +61298887600 21/26 00 0 A N N A RN N NR'3 Ci Ar, Alk in which: IO 1) A represents 00 (0 a) an amino group of formula NR1R 2 in which Ri and Rz, which are identical or different, represent hydrogen or a straight or branched alkyl Sgroup containing 1 to 4 carbon atoms or o b) a group OR 1 or SR 1 in which R, has the same meaning as above or c) an alkyl group containing 1 to 4 carbon atoms or a trifluoromethyl group or d) a hydrogen atom 2) R 3 and R'3, which are identical or different, represent independently of each other hydrogen or a CI-C4 alkyl group 3) Arl represents a nitrogen-containing aromatic ring representing: a) a quinoline optionally substituted with at least i) a group N(Ra)(Rb) in which Ra and Rb, which are identical or different, represent hydrogen or a CI-C4 alkyl radical or ii) a group ORa in which Ra is as defined above b) a quinoline possessing a nitrogen atom in quaternary form optionally substituted with a group selected from: 4-amino-, 4-methylamino- and 4- dimethylamino-, attached at the 4 position or c) a benzamidine or d) a pyridine attached at the 4-position 4) Alk represents a nonaromatic, optionally substituted, hydrocarbon chain as hereinbefore defined, chosen from alkyl (C1-C4), alkenyl (C2-C4), wherein the alkyl and alkenyl chain are linear or branched, cycloalkyl (C3-Ce), cycloalkenyl (C 3 -C 1 8 heterocycloalkyl (C 3 -C 18 and heterocycloalkyl (C3-C 18 including the nitrogen atom of the NR'3 group or a salt thereof. COMS ID No: ARCS-180904 Received by IP Australia: Time 13:18 Date 2008-02-27 27-Feb-2008 13:11 Watermark +61298887600 22/26 00 41 0 o 7. A compound according to claim 6, wherein Arj is chosen from: 4-amino-, 4- Smethylamino-, 4-dimethylamino- quinolyl, and quinolinium. CD) 8. A compound according to claim 6, wherein A is chosen from: a thiomethyl, amino, alkylamino and dialkylamino, in which the alkyl groups posssess 1 to 4 carbon atoms. O 0 9. A compound according to claim 6, wherein A represents a methylthio Cgroup. 0 0 10. A compound according to claim 6, wherein Alk represents an alkyl containing 2 to 3 linear or branched carbon atoms, wherein the alkyl is substituted with at least one of the following: i) an amino, alkylamino, arylamino, dialkylamino or diarylamino, or ii) an alkenyl unit containing 2 to 3 carbon atoms, which is substituted with at least one substituent selected from an amino, alkylamino, arylamino, dialkylamine, diarylamino and heterocyclyl, or iii) cycloalkyl unit containing from 4 to 7 carbon atoms. 11. A compound according to claim 6, wherein Alk represents a 2- (dialkylamino)ethyl, 3-(dialkylamino)propyl, 2-(N-alkyl-N-arylamino)ethyl or 3-(N- alkyl-N-arylamino)propyl in which the alkyl groups contain 1 to 4 carbon atoms and the aryl groups contain 5 to 18 carbon atoms. 12. A compound according to claim 6, characterized in that alk represents 2- (N-m-tolyl-N-ethylamino)ethyl. 13. A compound of claim 1, for use as a telomerase-inhibiting agent. 14. A compound according to any one of the preceding claims, for anticancer use. 15. A compound corresponding to the following formula COMS ID No: ARCS-180904 Received by IP Australia: Time 13:18 Date 2008-02-27 27-Feb-2008 13:12 Watermark +61298887600 23/26 00 42 0 0 A "RN N NR' Ar., alk 00 in which: N 1) A represents Sa) an amino group of formula NR 1 R 2 in which R 1 and R 2 which are S 5 identical or different, represent hydrogen or a straight or branched alkyl group containing 1 to 4 carbon atoms or b) a group OR 1 or SR, in which R 1 has the same meaning as above or c) an alkyl group containing 1 to 4 carbon atoms or a trifluoromethyl group or d) a hydrogen atom or e) a halogen atom chosen from fluorine, chlorine, bromine and iodine 2) R 3 and R' 3 which are identical or different, represent independently of each other a hydrogen or a C1-C4 alkyl group 3) Ar represents a nitrogen containing aromatic ring representing: a) a quinoline optionally substituted with at least i) a group N(Ra)(Rb) in which Ra and Rb, which are identical or different, represent hydrogen or a C1-C4 alkyl radical or ii) a group ORa in which Ra is as defined above b) a quinoline possessing a nitrogen atom in quaternary form optionally substituted with a group selected from: 4-amino-, 4-methylamino- and 4- dimethylamino-, attached at the 4 position or c) a benzamidine or d) a pyridine attached at the 4-position or fused with an aryl or heteroaryl group optionally substituted with a C1-C4 alkyl group 4) alk represents a nonaromatic, optionally substituted, hydrocarbon chain as hereinbefore defined, chosen from alkyl (C1-C4), alkenyl (C2-C4) wherein the alkyl and alkenyl chain are linear or branched, cycloalkyl (C3-CIa), cycloalkenyl (C3-C 18 or heterocycloalkyl (C3-C8) chain optionally including the nitrogen COMS ID No: ARCS-180904 Received by IP Australia: Time 13:18 Date 2008-02-27 27-Feb-2008 13:12 Watermark +61298887600 24/26 00 43 0 0 atom of the NR'3 group Sor a salt thereof C) wherein the nonaromatic hydrocarbon chain is optionally substituted with one or more atoms or radicals chosen from halogen atoms, hydroxyl, aryl, heteroaryl, alkyloxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino and/or arylamino, VB dialkylamino, diarylamino, amidino, guanidine, alkylcarbonlamino, 00 0arylcarbonlamino, carboxyl, alkyloxycarbonyl, aryloxycarbonyl, aminocarbonyl, Ci alkylaminocarbonyl, arylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonyl, 0 arycarbonyl, cyano and trifluoromethyl. 16. A compound according to claim 15, wherein Arl represents a group chosen from: 4-amino-, 4-methylamino-, 4-dimethylamino-quinolyl and quinolinium. 17. A compound according to claim 15, wherein group A represents a thiomethyl, amino, alkylamino or dialylamino, in which the alkyl groups possess 1 to 4 carbon atoms. 18. A compound according to claim 15, wherein R 1 and R2 represent hydrogen. 19. A compound according to claim 17, wherein A represents a methylthio group. A compound according to claim 15, wherein alk represents: i) an alkyl unit containing 2 to 3 linear or branched carbon atoms which is substituted with at least one substituent selected from: an amino, alkylamino, arylamino, dialkylamino and diarylamino. ii) an alkenyl unit containing 2 to 3 carbon atoms, which is substituted with at least one substituent selected from: an amino, alkylamino, arylamino, dialkylamino and diarylamino, or iii) a heterocyclyl unit containing from 4 to 7 carbon atoms. 21. A compound according to claim 15, wherein alk represents 2- COMS ID No: ARCS-180904 Received by IP Australia: Time 13:18 Date 2008-02-27 27-Feb-2008 13:13 Watermark +61298887600 25/26 00 44 0 0 (dialkylamino)ethyl, 3-(dialylamino)propyl, 2-(N-alkyl-N-arylamino)ethyl or 3-(N- alkyl-N-arylamino)propyl, in which the alkyl groups contain 1 to 4 carbon atoms C) and the aryl groups contain 5 to 18 carbon atoms. 22. A compound according to claim 15, wherein alk represents a 2-(N-m-tolyl- N-ethylamino)ethyl chain. 00 23. Use of the compound of claim 15, as pharmaceutical product for human Ci use. 0 O 24. A therapeutic combination consisting of a compound according to claim 1 and one or more other anticancer compounds. 25. A combination according to claim 24, wherein the one or more other anticancer compounds are chosen from: alkylating agents, platinum derivatives, antibiotic agents, antimicrotubule agents, anthracyclines, group I and II topoisomerases, fluoropyrimidines, cytidine analogues, adenosine analogues, L- asparaginase, hydroxyurea, trans-retinoic acid, suramine, irinotecan, topotecan, dexrazoxane, amifostine, herceptin, estrogenic and androgenic hormones. 26. Therapeutic combination consisting of a compound according to claim 1 and of radiation. 27. A combination according to claim 25 or claim 26, wherein each of the compounds or treatments is administered simultaneously, separately or sequentially.
- 28. A method of inhibiting telomerase activity, the method including administering to a patient a therapeutically effective amount of at least one compounds of any one of claims 1 to 22, wherein the level of telomerase activity in the patient following the administration is reduced relative to the level of telomerase activity existing prior to the administration. COMS ID No: ARCS-180904 Received by IP Australia: Time 13:18 Date 2008-02-27 27-Feb-2008 16:34 Watermark +61298887600 3/4 00 0 0
- 29. A method of treating a cancer, the method including administering to a patient a therapeutically effective amount of at least one compound of any one of 00 claims 1 to 22, wherein the level of telomerase activity following the administration is reduced relative to the level of telomerase activity existing prior to the administration. 00 AVENTIS PHARMA S.A. C WATERMARK PATENT TRADE MARK ATTORNEYS O 0 P22968AU00 ci COMS ID No: ARCS-180965 Received by IP Australia: Time 16:38 Date 2008-02-27
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR0100205A FR2819255B1 (en) | 2001-01-09 | 2001-01-09 | CHEMICAL DERIVATIVES AND THEIR APPLICATION AS ANTITELOMERASE AGENT |
FR01/00205 | 2001-01-09 | ||
PCT/FR2002/000057 WO2002055515A1 (en) | 2001-01-09 | 2002-01-09 | Chemical derivatives and their use as anti-telomerase agent |
Publications (2)
Publication Number | Publication Date |
---|---|
AU2002229859A1 AU2002229859A1 (en) | 2003-02-06 |
AU2002229859B2 true AU2002229859B2 (en) | 2008-03-13 |
Family
ID=8858610
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU2002229859A Expired - Fee Related AU2002229859B2 (en) | 2001-01-09 | 2002-01-09 | Chemical derivatives and their use as anti-telomerase agent |
Country Status (8)
Country | Link |
---|---|
EP (1) | EP1351957A1 (en) |
JP (1) | JP2004520350A (en) |
AU (1) | AU2002229859B2 (en) |
CA (1) | CA2433723A1 (en) |
FR (1) | FR2819255B1 (en) |
IL (1) | IL156794A0 (en) |
MX (1) | MXPA03005975A (en) |
WO (1) | WO2002055515A1 (en) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6887873B2 (en) | 2001-03-23 | 2005-05-03 | Aventis Pharma S.A. | Triazine derivatives and their application as antitelomerase agents |
US7173032B2 (en) * | 2001-09-21 | 2007-02-06 | Reddy Us Therapeutics, Inc. | Methods and compositions of novel triazine compounds |
FR2850970B1 (en) * | 2003-02-07 | 2006-07-07 | Aventis Pharma Sa | CHEMICAL DERIVATIVES BINDING VERY SPECIFIC TO G-QUADRUPLEX DNA STRUCTURES AND THEIR APPLICATION AS A SPECIFIC ANTICANCER AGENT |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9206768D0 (en) * | 1992-03-27 | 1992-05-13 | Jarman Michael | New compounds for use in the treatment of cancer |
US5767278A (en) * | 1995-10-06 | 1998-06-16 | Geron Corporation | Telomerase inhibitors |
JPH1160573A (en) * | 1997-08-22 | 1999-03-02 | Nippon Kayaku Co Ltd | Triazine derivative and telomerase inhibitor |
-
2001
- 2001-01-09 FR FR0100205A patent/FR2819255B1/en not_active Expired - Fee Related
-
2002
- 2002-01-09 MX MXPA03005975A patent/MXPA03005975A/en not_active Application Discontinuation
- 2002-01-09 WO PCT/FR2002/000057 patent/WO2002055515A1/en not_active Application Discontinuation
- 2002-01-09 EP EP02710956A patent/EP1351957A1/en not_active Withdrawn
- 2002-01-09 IL IL15679402A patent/IL156794A0/en unknown
- 2002-01-09 CA CA002433723A patent/CA2433723A1/en not_active Abandoned
- 2002-01-09 AU AU2002229859A patent/AU2002229859B2/en not_active Expired - Fee Related
- 2002-01-09 JP JP2002556184A patent/JP2004520350A/en not_active Abandoned
Also Published As
Publication number | Publication date |
---|---|
EP1351957A1 (en) | 2003-10-15 |
MXPA03005975A (en) | 2005-02-14 |
FR2819255A1 (en) | 2002-07-12 |
IL156794A0 (en) | 2004-02-08 |
WO2002055515A1 (en) | 2002-07-18 |
FR2819255B1 (en) | 2003-02-28 |
CA2433723A1 (en) | 2002-07-18 |
JP2004520350A (en) | 2004-07-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2179001A (en) | Arylamine derivatives and their use as anti-telomerase agent | |
US20090226411A1 (en) | Chemical derivatives and their application as antitelomerase agents | |
US6995175B2 (en) | Chemical derivatives and their application as antitelomerase agent | |
AU2002251140B2 (en) | Chemical derivatives and their use as anti-telomerase agent | |
US6858608B2 (en) | Chemical derivatives and their application as antitelomerase agents | |
AU2002229859B2 (en) | Chemical derivatives and their use as anti-telomerase agent | |
US20040053966A1 (en) | Chemical derivatives and their application as antitelomerase agent | |
MXPA05007648A (en) | Chemical derivatives binding very specifically with g-quadruplex dna structures and use thereof as a specific anti-cancer agent. | |
US20030013711A1 (en) | Chemical derivatives and their application as antitelomerase agents | |
US20020103169A1 (en) | Chemical derivatives and use thereof as antitelomerase agents | |
US20070232572A1 (en) | Chemical derivatives as antitelomerase agents which bind specifically to the G-quadruplex DNA structures and their application as a specific anticancer agent | |
US20040034023A1 (en) | Use of polycyclic aromatic compounds for making medicines capable of inhibiting telomerase | |
FR2822468A1 (en) | New arylamino-substituted triazine or diazine derivatives, used as telomerase inhibiting anticancer agents, by fixing the G-quadruplex structure of DNA or RNA | |
FR2821355A1 (en) | CHEMICAL DERIVATIVES AND THEIR APPLICATION AS ANTITELOMERASE AGENT | |
FR2825090A1 (en) | New compounds as telomerase inhibitors that fix the G-quadruplex structure of DNA or RNA, useful in the treatment of cancers | |
FR2801588A1 (en) | Diarylamino diazine and triazine derivatives are telomerase inhibitors and G-quadruplex stabilizers, useful in the treatment of cancers |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
MK25 | Application lapsed reg. 22.2i(2) - failure to pay acceptance fee |