CN113087658B - Compound with heat shock protein 70 inhibitory activity and application thereof - Google Patents
Compound with heat shock protein 70 inhibitory activity and application thereof Download PDFInfo
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- CN113087658B CN113087658B CN202110365441.1A CN202110365441A CN113087658B CN 113087658 B CN113087658 B CN 113087658B CN 202110365441 A CN202110365441 A CN 202110365441A CN 113087658 B CN113087658 B CN 113087658B
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- heat shock
- shock protein
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 42
- 102000018932 HSP70 Heat-Shock Proteins Human genes 0.000 title claims abstract description 25
- 108010027992 HSP70 Heat-Shock Proteins Proteins 0.000 title claims abstract description 25
- 230000002401 inhibitory effect Effects 0.000 title claims abstract description 19
- 239000003814 drug Substances 0.000 claims abstract description 3
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 abstract description 20
- 229960003180 glutathione Drugs 0.000 abstract description 10
- 238000006243 chemical reaction Methods 0.000 abstract description 9
- 230000000694 effects Effects 0.000 abstract description 8
- 239000003112 inhibitor Substances 0.000 abstract description 7
- 108010024636 Glutathione Proteins 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 2
- 230000000052 comparative effect Effects 0.000 description 8
- 101100507655 Canis lupus familiaris HSPA1 gene Proteins 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 5
- 239000000126 substance Substances 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- UEXCJVNBTNXOEH-UHFFFAOYSA-N Ethynylbenzene Chemical group C#CC1=CC=CC=C1 UEXCJVNBTNXOEH-UHFFFAOYSA-N 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000002773 nucleotide Substances 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000012795 verification Methods 0.000 description 2
- 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
- 241000894006 Bacteria Species 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 238000003734 CellTiter-Glo Luminescent Cell Viability Assay Methods 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 101150092565 DOHH gene Proteins 0.000 description 1
- 101100278318 Dictyostelium discoideum dohh-2 gene Proteins 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- QAHVHSLSRLSVGS-UHFFFAOYSA-N sulfamoyl chloride Chemical compound NS(Cl)(=O)=O QAHVHSLSRLSVGS-UHFFFAOYSA-N 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 238000002371 ultraviolet--visible spectrum Methods 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/32—Sulfur atoms
- C07D213/34—Sulfur atoms to which a second hetero atom is attached
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
- C07C311/12—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings
- C07C311/13—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings the carbon skeleton containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
- C07D295/26—Sulfur atoms
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Peptides Or Proteins (AREA)
Abstract
The invention belongs to the technical field of medicines, and particularly provides a compound with heat shock protein 70 inhibitory activity and application thereof. The compound comprises at least one of three compounds in the specification. The compound of the invention has weak reaction ability to glutathione and stronger binding ability to heat shock protein 70, has higher activity and lower side effect in a complex biological system, and can be used as an inhibitor.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a compound with heat shock protein 70 inhibitory activity and application thereof.
Background
Heat shock protein 70(Hsp70) is widely distributed in various organisms, and its sequence and structure are highly conserved from lower bacteria to higher mammals. Hsp70 consists of an amino-terminal nucleotide binding domain, a carboxy-terminal Substrate Binding Domain (SBD), and a hydrophobic flexible chain of about ten amino acid residues connected between the nucleotide binding domain and the substrate binding domain. Among them, the substrate binding domain SBD can be divided into a β -sheet rich SBD β subdomain and an α -helix rich SBD α subdomain.
There are reports in the literature that,
(PES) is an inhibitor of Hsp70 and is thought to be likely to bind to SBD of Hsp 70. PES can selectively kill tumor cells, basically has no toxicity to normal cells under the same concentration, and can inhibit the activity of tumor cells such as leukemia, lymphoma, bladder cancer, pancreatic cancer, non-small cell lung cancer, cervical cancer and the like, but PES also has strong reaction capability to Glutathione (GSH) which is abundantly present in vivo, so that an inhibitor which has weak reaction performance to GSH and maintains or improves the binding capability to Hsp70 needs to be developed so as to improve the activity of a compound in a complex biological system and reduce possible side effects.
Disclosure of Invention
The embodiment of the invention provides a compound with heat shock protein 70 inhibitory activity and application thereof, and aims to provide a compound with weak glutathione response capability and stronger binding capability to heat shock protein 70.
The invention is realized by the following steps:
a compound having heat shock protein 70 inhibitory activity, said compound comprising at least one of the following three compounds:
correspondingly, the compound with heat shock protein 70 inhibitory activity is applied as an inhibitor.
Optionally, the use is of the compound having heat shock protein 70 inhibitory activity as an inhibitor of heat shock protein 70.
The invention has the following beneficial effects:
compared with the prior art, the compound with the heat shock protein 70 inhibitory activity provided by the invention has weak reaction capability on glutathione, stronger binding capability on the heat shock protein 70, higher activity and lower side effect in a complex biological system, thus being capable of being used as the heat shock protein 70 inhibitor.
Detailed Description
In order to make the technical problems, technical solutions and advantageous effects to be solved by the present invention more clearly apparent, the present invention is further described in detail below with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
The compound with heat shock protein 70 inhibitory activity provided by the embodiment of the invention has the following structure:
the compound of the present invention can be obtained by the following reaction scheme.
The reaction formula is as follows:
the reaction formula starts from phenylacetylene and derivatives thereof, bis-trimethylsilyl amino Lithium (LiHMDS) is added at low temperature, and then chlorosulfonamide is added to obtain a target product.
To better illustrate the technical solution of the present invention, the following examples are further described.
Example 1
A compound having heat shock protein 70 inhibitory activity, the compound having the chemical formula:
the compound of this example was prepared using the route of the above equation.
Example 2
A compound having heat shock protein 70 inhibitory activity, the compound having the chemical formula:
the compound of this example was prepared using the route of the above equation.
Example 3
A compound having heat shock protein 70 inhibitory activity, the compound having the chemical formula:
the compound of this example was prepared using the route of the above equation.
And (3) performance testing:
the compounds obtained in examples 1 to 3 were subjected to corresponding performance verification analysis, and a literature compound PES was used as a comparative example, and the specific verification process is as follows:
(1) method for detecting t of compound reacted with GSH by ultraviolet-visible spectrophotometry1/2：
In buffer (50mM Tris-HCl, pH 7.5,100mM KCl,5mM MgCl)2) 1mM GSH was mixed with 50. mu.M of any of the compounds of examples 1 to 3 and comparative examples, and UV-visible spectrum scanning (240nm to 340nm) was performed on a SHIMADZU UV-2600 instrument, and the spectrum was recorded every 5 minutes at 25 ℃ until the UV-Vis signal leveled off. Finally, the time course of the change in concentration with increasing reaction product was monitored, fitted, by recording the absorption at 280nm, and the results are recorded in table 1.
(2) Fluorescence density-centric assay for t of compound reacted with Hsp701/2：
1mM of any of the compounds of examples 1 to 3 and comparative examples were mixed rapidly with 10. mu. MWT-hHsp70 in buffer, and a hHsp70 endogenous fluorescence scan was performed on a Hitachi F-4500 instrument with 295nm excitation light, intensity of emitted light at 310nm to 380nm was recorded, and spectra were recorded every 5 minutes at 25 ℃ until the endogenous fluorescence signal leveled off. Using the formula
The fluorescence density Center (CSM) of the endogenous fluorescence was calculated and the time course of the change of the fluorescence density center with the reaction was fitted and the results are reported in Table 1.
(3) Test procedure for detecting compounds inhibiting the proliferation of cancer cells DoHH 2:
DOHH2 cells were cultured in RMPI-1640(Gibco) supplemented with 10% fetal bovine serum (FBS, Gibco). Cells were seeded in 96-well plates (3000 cells/well), treated with various concentrations of any of the compounds of examples 1 to 3 and comparative examples for 72 hours, and then measured using the Cell Titer-Glo luminescent Cell viability assay (Promega), with the results reported in table 1.
TABLE 1
As can be seen from Table 1, the compounds of examples 1 to 3 effectively reduced the reactivity with GSH as shown by t in column 31/2T is significantly greater (even undetected) than for comparative example (PES)1/2(ii) a But still effectively retained the reactivity with Hsp70 as shown in column 4, t1/2T less than or equal to that of comparative example (PES)1/2(ii) a Furthermore, examples 1 to 3 also have potent tumor cell inhibitory activity, as shown in GI of column 550GI lower than that of comparative example (PES)50. These data indicate that the compounds of examples 1 to 3 can better maintain the efficiency of targeting Hsp70 in complex organisms, reducing the likelihood of off-target, compared to the comparative example PES.
In conclusion, the compound with heat shock protein 70 inhibitory activity designed and synthesized by the invention has weak reaction capability to glutathione and stronger binding capability to heat shock protein 70, and can be used as an inhibitor of heat shock protein 70.
The above description is intended to be illustrative of the preferred embodiment of the present invention and should not be taken as limiting the invention, but rather, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the invention.
Claims (2)
1. A compound having heat shock protein 70 inhibitory activity, wherein said compound is selected from at least one of the following two compounds:
2. the use of the compound having heat shock protein 70 inhibitory activity according to claim 1 in the preparation of a medicament for inhibiting heat shock protein 70.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202110365441.1A CN113087658B (en) | 2021-04-06 | 2021-04-06 | Compound with heat shock protein 70 inhibitory activity and application thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202110365441.1A CN113087658B (en) | 2021-04-06 | 2021-04-06 | Compound with heat shock protein 70 inhibitory activity and application thereof |
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| Publication Number | Publication Date |
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| CN113087658A CN113087658A (en) | 2021-07-09 |
| CN113087658B true CN113087658B (en) | 2022-05-17 |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110189125A1 (en) * | 2008-09-19 | 2011-08-04 | Trustees Of The University Of Pennsylvania | Modulators of HSP70/DnaK Function and Methods of Use Thereof |
| CN105439972A (en) * | 2015-07-17 | 2016-03-30 | 中国科学院广州生物医药与健康研究院 | Heat shock protein inhibitor and preparation method and application thereof |
| US20170014434A1 (en) * | 2014-02-26 | 2017-01-19 | The Trustees Of The University Of Pennsylvania | Small Molecule HSP70 Inhibitors |
| CN107540624A (en) * | 2016-06-29 | 2018-01-05 | 广州市恒诺康医药科技有限公司 | Heat shock protein inhibitors and its preparation method and application |
| CN109364045A (en) * | 2018-10-21 | 2019-02-22 | 郑州大学第附属医院 | A kind of inhibitor of heat shock protein 90 and the application in terms of liver cancer treatment |
-
2021
- 2021-04-06 CN CN202110365441.1A patent/CN113087658B/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110189125A1 (en) * | 2008-09-19 | 2011-08-04 | Trustees Of The University Of Pennsylvania | Modulators of HSP70/DnaK Function and Methods of Use Thereof |
| US20170014434A1 (en) * | 2014-02-26 | 2017-01-19 | The Trustees Of The University Of Pennsylvania | Small Molecule HSP70 Inhibitors |
| CN105439972A (en) * | 2015-07-17 | 2016-03-30 | 中国科学院广州生物医药与健康研究院 | Heat shock protein inhibitor and preparation method and application thereof |
| CN107540624A (en) * | 2016-06-29 | 2018-01-05 | 广州市恒诺康医药科技有限公司 | Heat shock protein inhibitors and its preparation method and application |
| CN109364045A (en) * | 2018-10-21 | 2019-02-22 | 郑州大学第附属医院 | A kind of inhibitor of heat shock protein 90 and the application in terms of liver cancer treatment |
Non-Patent Citations (1)
| Title |
|---|
| Hepatoselectivity of statins: Design and synthesis of 4-sulfamoyl pyrroles as HMG-CoA reductase inhibitors;William K. C. Park et al.;《Bioorganic & Medicinal Chemistry Letters》;20071205;第18卷(第3期);1151-1156 * |
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| CN113087658A (en) | 2021-07-09 |
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