Replication protein A targeted platinum compound

A technology for replicating proteins and compounds, which is applied to platinum-based organic compounds, platinum-group organic compounds, and compounds containing Group 8/9/10/18 elements of the periodic table, etc. Reduce the curative effect of chemotherapy drugs and other problems, achieve excellent anti-tumor activity, reduce reactivity and toxicity, and overcome drug resistance

Active Publication Date: 2021-03-05
TIANJIN MEDICAL UNIV
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Problems solved by technology

The effect of RPA on repair methods such as NER and HR reduces the efficacy of platinum-based chemotherapy drugs and enhances the drug resistance of tumor cells (Shuck S C, Turchi J J. Targeted inhibition of RPA reveals cytotoxic activity, synergy with chemotherapeutic DNA damaging agents and insight into cellular function [J]. Cancer Research, 2010, 70(8): 3189.)

Method used

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  • Replication protein A targeted platinum compound
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  • Replication protein A targeted platinum compound

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Embodiment 1-based on the synthesis and characterization of novel platinum-based Pt (IV) RPA small molecule inhibitor prodrugs, as attached figure 1 -30

[0054] Accurately weigh cisplatin (100mg, 0.34mmol) in a 10mL round bottom flask, slowly add 2mL of 30% H 2 o 2 After the reaction solution was refluxed at 75° C. in the dark for 5 h, the reaction solution was kept at 4° C. overnight in the dark. After standing still, the suspension was separated by centrifugation to obtain a yellow solid precipitate, which was washed with distilled water, ethanol and ether, and then vacuum-dried to obtain 89 mg of yellow solid powder of substance 2, with a yield of 88.28%.

[0055]

[0056] Accurately weigh substance 2 (50.11 mg, 0.15 mmol) into a 25 mL round bottom flask, add DMSO to dissolve, and stir the reaction solution at 60° C. under the protection of argon for 30 min in the dark until the solution is clear. In addition, accurately weigh the substances TDRL-551 (0.15mm...

Embodiment 2

[0073] Embodiment 2—compound (3a-3e) and antitumor activity evaluation of cisplatin

[0074] MTT colorimetry is one of the methods used to detect cell growth and survival in experimental research. In the mitochondria of living cells, exogenous MTT can be reduced by intracellular succinate dehydrogenase to formazan, a purple-blue crystal formazan that is insoluble in water. Formazan is deposited in the cytoplasm of cells, but dead cells do not This phenomenon occurs. When formazan encounters DMSO, the formazan deposited in the cells will be dissolved by DMSO. The optical density value (OD value) of formazan at a wavelength of 570nm was detected by a microplate reader to indirectly reflect the number of living cells, the amount of MTT crystals formed was positively correlated with the number of living cells, and the IC was calculated by using Graphpad Prism 6 software to process the data 50 Value and plot, IC 50 The value refers to the half-inhibitory concentration of the mea...

Embodiment 3

[0078] We use cell cycle and apoptosis experiments to verify the anti-tumor activity of the novel platinum (IV) RPA small molecule inhibitor prodrug of the present invention. The cell cycle refers to the process of cells from the completion of one mitosis to the end of the next mitosis. It can be divided into three phases: G0 / G1 phase, S phase, and G2 / M phase. The G0 / G1 phase is the preparation period for mitosis, and the synthesis of RNA and related proteins is doubled to make necessary preparations for the synthesis of genetic material DNA; the S phase is the DNA synthesis phase, in which all DNA synthesis is completed; the G2 / M phase is During protein synthesis and mitosis, the synthesized chromosomes and other components are evenly distributed to two newly formed daughter cells, and the above process repeats itself to realize cell proliferation. The cell cycle plays a very important role in the regulation of cell proliferation and apoptosis.

[0079] as attached Figure...

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Abstract

The invention discloses replication protein A targeted platinum compound. Tetravalent cis-platinum is combined with an RPA (replication protein A) small-molecule inhibitor through an axial hydroxyl position, and an aliphatic hydrocarbon chain is introduced, and therefore, a series of platinum anti-tumor compounds can be synthesized. The platinum anti-tumor compounds have the advantages of inhibiting the activity and tumor specificity selection of the RPA, so that the platinum anti-tumor compounds show the anti-tumor activity superior to that of a classic platinum drug, and shows the potentialof overcoming the drug resistance of a clinical platinum drug.

Description

technical field [0001] The invention belongs to the technical field of platinum compounds, and more specifically relates to a class of DNA damage repair-based platinum compound anti-tumor activity, reducing toxic and side effects and overcoming clinical platinum drug resistance. Background technique [0002] Malignant tumors are always a threat to human health and life safety, and are of great value and significance to the treatment and research of malignant tumors. Improving the targeting, selectivity and safety of chemotherapy drugs is the current research and development trend of new anti-tumor drugs. Platinum drugs represented by cisplatin (CDDP) play a vital role in clinical tumor treatment (such as ovarian cancer, non-small cell lung cancer), and more than 50% of tumor chemotherapy requires the participation of platinum drugs. However, tumor drug resistance greatly limits the development of such drugs. More than 80% of patients with epithelial ovarian cancer have tum...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F15/00A61P35/00
CPCC07F15/0093A61P35/00
Inventor 乔鑫徐靖源徐令文
Owner TIANJIN MEDICAL UNIV
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