CN102603812B - A kind of Binuclear platinum (II) – Zoledronic acid title complex and Synthesis and applications thereof - Google Patents
A kind of Binuclear platinum (II) – Zoledronic acid title complex and Synthesis and applications thereof Download PDFInfo
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Abstract
The invention discloses a kind of Binuclear platinum (II) – Zoledronic acid title complex, its general structure is (I), the invention also discloses its preparation method, comprise the preparation of diiodo-quadrol platinum complex, the preparation of sulfate radical quadrol platinum complex and obtaining of final product; (II) – Zoledronic acid title complex is used for the treatment of osteosarcoma and lung cancer to Binuclear platinum proposed by the invention.(II) – Zoledronic acid title complex has that good water solubility, toxic side effect and resistance are low to Binuclear platinum disclosed by the invention, the advantage of Bone targeting function and antitumour activity excellence.
Description
Technical field
The present invention relates to a kind of cancer therapy drug, particularly, relate to a kind of Binuclear platinum (II) – Zoledronic acid title complex and Synthesis and applications thereof.
Background technology
The health of the mankind in cancer serious threat, and the annual whole world about has 7,000,000 people to die from cancer.Osteosarcoma is one of malignant tumour being difficult to healing and pain most, and chemotherapy is one of osteosarcomatous Main Means of current clinical treatment.First-generation platinum-containing anticancer drug-cis-platinum be one of osteosarcomatous main selection for the treatment of, but it also exists serious resistance and toxic side effect (as renal toxicity, gastrointestinal toxicity etc.), and these problems and cis-platinum tumor-selective difference is closely related.Although have developed again s-generation platinum-containing anticancer drug carboplatin afterwards, third generation platinum-containing anticancer drug oxaliplatin, overcomes the shortcoming of cis-platinum to a certain extent, as toxic side effect reduces, water-soluble raising, also have effect to the tumour cell of some resistance to cis-platinums, but due to structural similitude, still can not obviously improve with cis-platinum is the limitation (Liu Weiping that the classical platinum-containing anticancer drug of representative has, Zhang Yongli, Sun Jialin. Future Development of Platinum Anticancer Drugs [J]. precious metal .2005,26,47-52.).Therefore, we are necessary the classical structure activity relationship breaking through platinum-containing anticancer drug, find and have good Bone targeting optionally cancer therapy drug, thus improve the curative effect of the disease of skeletal system such as osteosarcoma, reduce the toxic side effect to other Organ and tissue.
Two banks is a compounds with P-C-P feature structure, this compounds has very high avidity for bone and other calcified tissues, bone metabolism active-site can be passed to preferentially, rapidly, thus absorbed by osteoclast, and then suppress maturation and the effect of osteoclast, suppress the bone Reabsorption of Osteoclasts mediate, be applied to the various bone related disease that treatment scleromalacia disease, osteoporosis and tumour cause.Bis phosphoric acid salt experienced by the development of three generations, Zoledronic acid (English name ZL) wherein in third generation bisphosphonates is the best bisphosphonate class of drugs of current comprehensive drug, there is bone avidity and the good therapeutic action (NevilleWebbeH of height, et, al.Theuseofzoledronicacidinthemanagementofmetastaticbone diseaseandhypercalcaemia [J] .Pallia.Med., 2003, 17, 539.), drug effect compares clodronate disodium, Rhodiola pamiro-alaica is strong 100 times, 1000 times (MatthewR.Smith.Osteoclasttargetedtherapyforprostatecance r:Bisphosphonatesandbeyond [J] .Urol.Oncol.:Semin.Orig.Investig.2008s stronger than etidronate disodium, 26, 420-425.).Zoledronic acid dosage is little, and the time is short, and interval time is long, evident in efficacy, untoward reaction few (LiEC, et, al.Zoledronicacid:anewparenteralbisphosphonate [J] .Clin.Ther., 2003,25,2669.).Therefore, Zoledronic acid becomes a kind of medicine being widely used in clinically treating bone related disease, the metal complexes of Zoledronic acid and derivative thereof still shows good Bone targeting simultaneously, bibliographical information (1. MakbuleAsikoglu has been shown in by the diagnosis and treatment medicine utilizing Zoledronic acid to carry out developing Skeletal system relative disease as Bone targeting carrier, et, al.Therabbitbiodistributionofatherapeuticdoseofzoledroni cacidlabeledwithTc-99m [J] .Appl.Radiat.Isot., 2009,67,1616-1621; 2. MajkowskaA, NevesM, AntunesI, BilewiczA..Complexesoflowenergybetaemitters
47scand
177luwithzoledronicacidforbonepaintherapy [J] .Appl.Radiat.Isot., 2009,67,11-13; 3. JianguoLin, et, al.Preparationandinvivobiologicalinvestigationsonanovelr adioligandforbonescanning:technetium-99m-labeledzoledron icacidderivative [J] .Nucl.Med.Biol., 2011,38,619-629.).
In order to the antitumous effect of the Bone targeting of bis-phosphonic acids compounds and platinum complexes effectively being combined, improve the curative effect of the relative diseases such as osteosarcoma, Chinese scholars expands in this respect to be studied widely, and has made fruitful work.2010, the people such as ZuqinXue have reported the (preparation of II) – diphosphonic acid complex of a series of platinum, some of them title complex has good restraining effect (ZuqinXue to human osteosarcoma, ovarian cancer cell, et, al.Platinum (II) compoundsbearingbone-targetinggroup:synthesis, crystalstructureandantitumoractivity [J] .Chem.Commun., 2010,46,1212-1214.).In addition, NicolaMargiotta seminar since two thousand seven reports an eka-platinium (synthesis of II) – diphosphonic acid complex and the research of biological property thereof, experimental result shows that this dinuclear platinum complex all has stronger restraining effect to tumour cells such as people's lung cancer, also restraining effect is had to the human tumor cell line of some resistance to cis-platinums, and the adsorption rate of this dinuclear platinum complex to hydroxyapatite (major ingredient of bone) can reach 96%, illustrate that the existing good anti-tumor activity of this platinum complex has again stronger Bone targeting (1. NicolaMargiotta, et, al.Bisphosphonatecomplexationandcalciumdopinginsilicaxer ogelsasacombinedstrategyforlocalandcontrolledreleaseofac tiveplatinumantitumorcompounds [J] .DaltonTrans., 2007, 3131-3139, 2. NicolaMargiotta, et, al.Synthesis, characterization, andcytotoxicityofdinuclearplatinum-bisphosphonatecomplex estobeusedasprodrugsinthelocaltreatmentofbonetumours [J] .DaltonTrans, 2009,10904-10913, 3. MicheleIafisco, et, al.Smartdeliveryofantitumoralplatinumcomplexesfrombiomim etichydroxyapatitenanocrystals [J] .J.Mater.Chem., 2009,19,8385-8392.).
In a word, prior art does not also find Zoledronic acid (high close bone, dosage is little, time is short, interval time is long, evident in efficacy, and untoward reaction is few) be incorporated in platinum (II) title complex, play the dual function of its Bone targeting and treatment, strengthen the application of platinum-bis-phosphonic acids title complex anticancer function.
Summary of the invention
The technical problem to be solved in the present invention overcomes existing defect, and (II) – Zoledronic acid title complex, it has, and good water solubility, toxic side effect and resistance are low, the advantage of Bone targeting function and antitumour activity excellence to provide a kind of novel Binuclear platinum.
In order to solve the problems of the technologies described above, the invention provides following technical scheme:
A kind of Binuclear platinum (II) – Zoledronic acid title complex, has following structural formula (I):
（I）
The present invention propose Binuclear platinum (preparation method of II) – Zoledronic acid title complex, comprises the following steps:
(1) preparation of diiodo-quadrol platinum complex: potassium chloroplatinite and excessive potassiumiodide 40 DEG C of low-grade fevers, crosses after reaction and filters insolubles, add reacting ethylenediamine in gained solution, leaves and takes throw out washing dry; Obtained diiodo-quadrol platinum complex is cis-compound, also can be expressed as cis-Pt (en) I
2;
(2) sulfate radical quadrol platinum complex [Pt (en) (OSO
3) (H
2o) preparation]: under lucifuge condition, step (1) products therefrom and Sulfuric acid disilver salt react and spend the night, and removing precipitation, evaporate to dryness obtains [Pt (en) (OSO
3) (H
2o)];
(3) Binuclear platinum (obtaining of II) – Zoledronic acid title complex: step (2) gained [Pt (en) (OSO
3) (H
2o) after] reacting with Zoledronic acid barium, Ba (OH)
2regulate PH to 5.0, remove precipitation, then add H
2sO
4regulate pH to 1.5-2.0, obtained Binuclear platinum (II) – Zoledronic acid title complex.
The reaction formula of step (3) is:
Binuclear platinum (the application of II) – Zoledronic acid title complex in preparation treatment osteosarcoma and lung-cancer medicament that the present invention proposes.
In sum, its total reaction route is:
Wherein, being abbreviated as in above-mentioned reaction formula:
Binuclear platinum (II) – Zoledronic acid title complex: [{ Pt (en) }
2zL];
Quadrol: en;
Zoledronic acid: ZL;
Zoledronic acid barium: Ba-ZL;
Potassium chloroplatinite: K
2ptCl
4;
Sulfate radical quadrol platinum complex: [Pt (en) (OSO
3) (H
2o)];
Diiodo-quadrol platinum complex (cis): cis-Pt (en) I
2.
The present invention has following beneficial effect:
The comprehensive advantage of Zoledronic acid part and the feature of platinum complex, we have designed and synthesized a kind of novel Binuclear platinum, and (II) – Zoledronic acid title complex, is incorporated into the Zoledronic acid with outstanding clinical value in such medicine as part first.Expect that this dinuclear platinum complex has high bone avidity due to the existence of Zoledronic acid on the one hand, bone metabolism active-site can be passed to fast, thus there is Bone targeting function and the result for the treatment of of excellent performance, on the other hand there is again good antitumour activity, this platinum complex can be combined with target molecule DNA, produces in chain afterwards or interchain linkage, and then interference DNA normal replication, finally cause cancer cell death, and have lower toxic side effect and resistance compared to cis-platinum.By initial in vitro biological experiment, we have screened two kinds of human tumor cell line: osteosarcoma U2-OS and lung cancer A549 cell, find that this compound has obvious restraining effect for the propagation of these two kinds of cells, thus can as a kind of potential Bone targeting cancer therapy drug.
Embodiment
product and preparation embodiment:
Binuclear platinum (II) – Zoledronic acid title complex and preparation thereof:
(1) diiodo-quadrol platinum complex cis-Pt (en) I
2preparation:
By water-soluble for potassium chloroplatinite (0.415g, 1mmol), under agitation, dropwise add excessive liquor kalii iodide (1.328g, 8mmol), at 40 DEG C, react 20-40 minute, elimination insolubles.Under agitation, dropwise in filtrate, add quadrol (0.057g, 0.95mmol), at 40 DEG C, react 4-6 hour, filter to obtain throw out, with frozen water, ice washed with diethylether, vacuum-drying, obtains dark yellow solid 0.4736g, and productive rate is 94.94%.
(2) intermediate product [Pt (en) (OSO
3) (H
2o) preparation]:
By cis-[Pt (en) I
2] (0.509g, 1mmol) be suspended in 20ml water, adds Sulfuric acid disilver salt (0.3058g0.98mmol), at 25 DEG C, stirring is spent the night, and cross and filter precipitation, filtrate decompression distillation and concentration is to original volume half, filter with millipore filter (0.22 μm), removing insolubles, then underpressure distillation is closely dry, then vacuum-drying, obtain bright yellow solid powder 0.3297g, productive rate is 91.17%.
(3) Binuclear platinum (producing of II) – Zoledronic acid title complex:
Zoledronic acid solid (0.0272g, 0.1mmol) is dissolved in 5ml water, 25 DEG C, N
2protection, instills baryta water (0.0171g, 0.1mmol), produces white opacity immediately under agitation condition, maintain and stir 10-20 minute, obtain white solid and be Zoledronic acid barium salt, without other process.
Above-mentioned suspension liquid is placed in ice bath, and controlling temperature in reaction vessel is 0-5 DEG C, gets [Pt (en) (OSO
3) (H
2o)] (0.0738g, 0.2mmol) is dissolved in 2ml water completely, at N
2in the above-mentioned reaction solution of the lower instillation of protection, stir 4-5 hour, stopped reaction.Centrifugal (15min, 2000rpm) isolates supernatant liquid, and 30-35 DEG C of underpressure distillation is to the half of original volume, and with millipore filter (0.22 μm) removing insolubles, underpressure distillation is concentrated into 1-2mL solution.
In above-mentioned solution, add Ba (OH)
2(0.5M) regulate pH=5.0, centrifugation, then add H
2sO
4regulate pH=1.5-2.0, obtain 65.3mg greenish yellow solid, productive rate is 83.93%.
In above-mentioned steps (3), add Ba (OH)
2adjust ph, both can allow Zoledronic acid exist with anionic form, again can with [Pt (en) (OSO
3) (H
2o) sulfate radical] forms precipitation, impels coordination reaction to carry out smoothly, generates stable target product [{ Pt (en) }
2zL].Add appropriate H afterwards
2sO
4in order to remove excessive barium ion, thus separate out the higher pure target compound of productive rate.
product detects:
Target product is respectively through the confirmation of ultimate analysis, mass spectrum, infrared spectra and proton nmr spectra.
1, [{ Pt (en) }
2zL] ultimate analysis (C
9h
22n
6o
7p
2pt
2, ElementarVarioELIIIanalyzer, Germany):
2、[{Pt(en)}
2ZL]ESI-MS（WatersPlatformZMD4000,U.S.A.）：[M-H]=776.8(100%)
3, [{ Pt (en) }
2zL] infrared spectra (cm
-1, KBr compressing tablet, NicoletNexus470, Thermo): 3406(υ O-H), 3280,3205(υ N-H), 3153(υ N=C-H), 2959(υ C-H), 1629(υ C=N), 1566(υ C=C), 1466(δ C-H), 1288(υ P=O), 1128,1052(υ P-O), 570(υ Pt-O);
4、[{Pt(en)}
2ZL]
1H-NMR（D
2O,TMS,400MHz,BrukerDRX-500spectrometer,Germany）：
application Example
Drug efficacy evaluation:
Experimental technique: MTT colorimetry
Cell strain: human osteosarcoma U2-OS cell, typeⅡ pneumocyte
Experimental design:
The cultivation of cell: the DMEM nutrient solution (RPMI-1640) of U2-OS cell (A549 cell) containing 100,000 U/L penicillin, 100,000 U/L Streptomycin sulphates, 10% foetal calf serum, in 37 DEG C, containing 5%CO
2incubator in cultivate.
The mensuration of cell inhibitory rate: with trypsin digestion cell, being made into cell suspension by conventional medium, adding 96 orifice plates (for preventing fringing effect, peripheral hole does not add cell), returns to zero, as blank by the blank well only adding nutrient solution and do not add cell.Remain every hole and add 100 μ LU2-OS, A549 cell suspensions, cell implantation concentrations is 7 × 10
7/ L.At 37 DEG C, containing 5%CO
2incubator in cultivate after 24 hours, test group and control group add [{ Pt (en) } of 100 μ L respectively
2zL] solution (concentration is divided into 8 groups: 5 ~ 100 μMs) and 100 μ L nutrient solutions, often group arranges 8 parallel holes.Continue cultivation after 72 hours, adding 20 μ LMTT(concentration is 5mg/mL) solution, put into incubator and continue cultivation after 4 hours, stop cultivating, carefully absorb supernatant liquor, add 100 μ L methyl-sulphoxides (DMSO), concussion 10min is to dissolving completely.Measure every hole absorbance A value by enzyme linked immunological microplate reader at 490nm, calculate [{ Pt (en) } with return law of the straight line
2zL] half-inhibition concentration (IC
50) value (SPSS software), often group experiment repetition 3 times.
experimental analysis:
1, [{ Pt (en) }
2zL] extracorporeal inhibiting rate (%) to human osteosarcoma U2-OS cell (72h):
2, [{ Pt (en) }
2zL] extracorporeal inhibiting rate (%) to typeⅡ pneumocyte (72h):
Result shows:
[{ Pt (en) }
2zL] IC to U2-OS and A549 cell
50value is respectively 22.98 μMs and 34.63 μMs.Chemical feeding quantity is 100 μMs, and during effect 72h, being 88.17% to the inhibiting rate of U2-OS cell, is 94.57% to the inhibiting rate of A549 cell, illustrates [{ Pt (en) }
2zL] to these two kinds of human tumor cell lines, there is obvious restraining effect, be expected to become a kind of Bone targeting antitumor drug with better application prospect.
Last it is noted that the foregoing is only the preferred embodiments of the present invention, be not limited to the present invention, although with reference to previous embodiment to invention has been detailed description, for a person skilled in the art, it still can be modified to the technical scheme described in foregoing embodiments, or carries out equivalent replacement to wherein portion of techniques feature.Within the spirit and principles in the present invention all, any amendment done, equivalent replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (3)
1. Binuclear platinum (II) – Zoledronic acid title complex, has following structural formula (I):
（I）。
2. Binuclear platinum according to claim 1 (preparation method of II) – Zoledronic acid title complex, comprises the following steps:
(1) preparation of diiodo-quadrol platinum complex: potassium chloroplatinite and excessive potassiumiodide 40 DEG C of low-grade fevers, crosses after reaction and filters insolubles, add reacting ethylenediamine in gained solution, leaves and takes throw out washing dry;
(2) preparation of sulfate radical quadrol platinum complex: under lucifuge condition, step (1) products therefrom and Sulfuric acid disilver salt react and spend the night, removing precipitation, and evaporate to dryness obtains sulfate radical quadrol platinum complex;
(3) Binuclear platinum (obtaining of II) – Zoledronic acid title complex: after step (2) gained sulfate radical quadrol platinum complex and Zoledronic acid barium react, Ba (OH)
2regulate pH to 5.0, remove precipitation, then add H
2sO
4regulate pH to 1.5-2.0, obtained Binuclear platinum (II) – Zoledronic acid title complex.
3. the Binuclear platinum according to claim 1 (application of II) – Zoledronic acid title complex in preparation treatment osteosarcoma and lung-cancer medicament.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5288887A (en) * | 1988-11-22 | 1994-02-22 | Board Of Regents, The University Texas System | Diamine platinum(IV) complexes having mixed carboxylate ligands as antitumor agents |
| US20060173185A1 (en) * | 2003-06-27 | 2006-08-03 | Akira Odani | Bisphosphonate complexes |
| CN101985456A (en) * | 2010-07-02 | 2011-03-16 | 江苏省原子医学研究所 | Bone-seeking 99mTc-IPrDP coordination compound as well as preparation method and application thereof |
-
2012
- 2012-03-09 CN CN201210061319.6A patent/CN102603812B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5288887A (en) * | 1988-11-22 | 1994-02-22 | Board Of Regents, The University Texas System | Diamine platinum(IV) complexes having mixed carboxylate ligands as antitumor agents |
| US5288887B1 (en) * | 1988-11-22 | 1996-03-12 | Reagents The University Of Tex | Diamine platinum(iv) complexes having mixed carboxylate ligands as antitumor agents |
| US20060173185A1 (en) * | 2003-06-27 | 2006-08-03 | Akira Odani | Bisphosphonate complexes |
| CN101985456A (en) * | 2010-07-02 | 2011-03-16 | 江苏省原子医学研究所 | Bone-seeking 99mTc-IPrDP coordination compound as well as preparation method and application thereof |
Non-Patent Citations (3)
| Title |
|---|
| A new dinuclear platinum complex with a nitrogen-containing geminal bisphosphonate as potential anticancer compound specifically targeted to bone tissues;Nicola Margiotta等,;《Journal of Inorganic Biochemistry》;20080726;第102卷(第12期);第2078-2086页, 尤其是标题、摘要、第2079-2080页图1以及2.3-2.5部分 * |
| Bisphosphonate complexation and calcium doping in silica xerogels as a combined strategy for local and controlled release of active platinum antitumor compounds;Nicola Margiotta等,;《Dalton Transactions》;20070619;第3131-3139页, 尤其是第3132页图2、第3133页左栏第2段 * |
| Synthesis, characterization, and cytotoxicity of dinuclear platinum-bisphosphonate complexes to be used as prodrugs in the local treatment of bone tumours;Nicola Margiotta等,;《Dalton Transactions》;20091116;第10904-10913页 * |
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