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Application of 2-cyano phenalenone compound in preparation of drug for treating drug-resistant tumors

A kind of technology of cyanophenacene and compound, applied in the field of medicinal chemistry

Active Publication Date: 2022-05-27
DALIAN UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the strategy of reversing drug resistance by targeting gene mutations also faces challenges. Tumor gene mutations are of high frequency, and new mutations are easily generated under the attack of targeted drugs
In addition, in drug-resistant tumors that are not dependent on gene mutations, cells escape anticancer drugs that target initial markers through a bypass activation mechanism, such as BCR-ABL non-mutation-dependent TKIs resistance, which cannot be resolved by upgrading TKIs

Method used

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  • Application of 2-cyano phenalenone compound in preparation of drug for treating drug-resistant tumors
  • Application of 2-cyano phenalenone compound in preparation of drug for treating drug-resistant tumors
  • Application of 2-cyano phenalenone compound in preparation of drug for treating drug-resistant tumors

Examples

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Effect test

Embodiment 1

[0032] Example 1: Detection of the ability of the compounds of the present invention to dissociate Hsp70 / Bim dimers in vitro by fluorescence polarization analysis

[0033] A BimBH3 peptide with 21 amino acids (amino acids: 79-99: QEDIIRNIARHLAQVGDSMDR) was synthesized and labeled with 6-carboxyfluorescein succinimidyl ester (FAM) as a fluorescent tag (FAM-Bim) at the N-terminus. The reaction system used in the competition binding experiment was GST-Hsp70 protein (300 nM), and FAM-Bim polypeptide (20 nM) dissolved in reaction buffer (100 mM K 3 PO 4 , pH 7.5; 100 μg / mL bovine gamma albumin; 0.02% sodium azide). In a 96-well plate, 100 µL of the reaction system was added to each well, followed by 1 µL of stock solutions of the compounds to be tested (0-10 mM) dissolved in DMSO at various concentrations, with a final concentration of 0-100 µM. At the same time, two control groups were set up. One control group contained only Hsp70 and FAM-Bim in the reaction system (equivalent ...

Embodiment 2

[0037] Example 2: Construction of different drug-resistant cell lines

[0038] According to the mRNA expression data of about 1,000 tumor cell lines of 22 tumor types collected in the CCLE database, we mainly select tumor cell lines such as breast cancer, lung cancer, leukemia, and liver cancer to establish tumor cell lines that are resistant to various anticancer drugs.

[0039] The drug concentration gradient method was used to establish tumor cell lines resistant to targeted drugs and chemotherapeutic drugs with different mechanisms, including chronic myeloid leukemia (CML) resistant to the third-generation BCR-ABL kinase inhibitor Ponatinib. ) cell lines K562 / PR, BV173 / PR; cisplatin (DDP)-resistant CML cell lines K562 / DDP, BV173 / DDP; Bcl-2 targeting drug Venetoclax-resistant B-cell lymphoma (NHL) cell lines and Acute lymphoma leukemia (ALL) cell lines Ri-1 / VR, RS4; 11 / VR; etoposide-resistant NHL and ALL cell lines Ri-1 / ER, RS4; 11 / ER; tamoxib Tamoxifen-resistant breast ca...

Embodiment 3

[0041] Example 3: Detection of apoptosis of tumor drug-resistant cell lines induced by the compounds of the present invention by flow cytometry

[0042] Apoptosis is one of the basic characteristics of cells, and it plays a very important role in embryonic development, tissue repair, and stability of the internal environment. In normal cells, phosphatidylserine (PS) is only distributed in the inner side of the lipid bilayer of the cell membrane, while in the early stage of apoptosis, the phosphatidylserine (PS) in the cell membrane is turned from the inside to the outside of the lipid membrane. Annexin V is a Ca-dependent phospholipid-binding protein with a molecular weight of 35-36 kD, which can specifically bind to PS that is flipped to the outside of the membrane during apoptosis with high affinity. Using FITC-labeled annexin V as a fluorescent probe, the occurrence of apoptosis can be detected by flow cytometry or fluorescence microscopy. PI (propidium iodide) is a DNA dy...

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Abstract

The invention discloses application of a 2-cyano phenalenone compound in preparation of drugs for treating drug-resistant tumors, and belongs to the technical field of medical chemistry. The 2-cyano phenalenone compound disclosed by the invention can induce apoptosis of tumor cells resistant to chemotherapeutic drugs such as cis-platinum and adriamycin and targeted anticancer drugs such as ponatinib, tamoxifen and Winatocork, so that the effects of inhibiting growth of the chemotherapeutic drugs and the targeted anticancer drug resistant cells and killing the chemotherapeutic drugs and the targeted anticancer drug resistant cells are achieved; the compound is an apoptosis inducer with very high activity, and can be used for preparing potential drugs for preventing and treating chemotherapeutic drugs and targeted anticancer drug-resistant tumors.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, in particular to the preparation of 2-cyanophenacene compounds in the preparation of anti-cisplatin, doxorubicin and other chemotherapeutic drugs and targets such as panatini, tamoxifen and venatorectin Drug application to anticancer drug-resistant tumors. Background technique [0002] Chemotherapy using cytotoxic drugs and targeted drug therapy for specific carcinogenic targets are the main drug treatment methods for cancer treatment at present. However, both chemotherapy and targeted drug therapy are faced with the problem of secondary drug resistance. The tumor eventually develops cross-resistance to a variety of anticancer drugs with different molecular mechanisms under the control of stress, and enters the terminal stage of almost "no drug available". . In addition to the drug pumping mechanism of the transporter P-gp, tumor cells often develop drug-resistant cell lines through...

Claims

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Application Information

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IPC IPC(8): A61K45/00A61K31/277A61K31/5375A61K31/495A61K31/4409A61P35/00A61P35/02
CPCA61K45/00A61K31/277A61K31/5375A61K31/495A61K31/4409A61P35/00A61P35/02Y02A50/30
Inventor 张志超高岐双王紫千宋婷
Owner DALIAN UNIV OF TECH
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