Application of 3-oxo-5 beta-steroid-4-dehydrogenase inhibitor

A dehydrogenase inhibitor, steroid technology, applied in the field of medicine, can solve problems such as no target mechanism

Pending Publication Date: 2020-10-13
武汉红猎生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

From 1999 to 2019, more than 50 ophiobolin compounds were reported to have cytotoxic activity. The National Cancer Institute of the United States tested the toxicity of ophiobolin A to 60 types of tumor cells, and the average half inhibitory rate was 70 nM. ophiobolin K also passed 11 kinds of In the test of tumor cells, the half inhibitory rate is between 4 nM and 650 nM. The inhibitory mechanism of ophiobolin compounds on tumors involves many aspects such as apoptosis, autophagy, and cell cycle arrest, but so far there is no recognized and credible one. specific target mechanism

Method used

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  • Application of 3-oxo-5 beta-steroid-4-dehydrogenase inhibitor
  • Application of 3-oxo-5 beta-steroid-4-dehydrogenase inhibitor
  • Application of 3-oxo-5 beta-steroid-4-dehydrogenase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Example 1 Test of anti-tumor activity

[0026] 1. Experimental samples and experimental methods

[0027] Configuration of the tested sample solution: The test sample is the above compound 1, accurately weigh an appropriate amount of sample, and configure it with DMSO to form a solution of the required concentration for activity testing.

[0028] Cell line and cell subculture: The viability test uses human liver cancer cells HepG2, SMMC7721, Bel7402, prostate cancer PC3 and its paclitaxel-resistant cells, and the cell culture medium is RPMI 1640 +10%FBS+1% (Penicillin-Streptomycin Solution) , Microglioma CHME-5, colon cancer HCT-116 use DMEM medium containing 10% FBS, SW579 cells use 10% FBSMPI-1640 medium, cultured in a 37︒C incubator with 5% carbon dioxide . The cell proliferation inhibitory activity test method adopts the MTT method.

[0029] 2. Experimental results

[0030] Table 1. The inhibitory ability of compound 1 on different tumor cells

[0031]

[0032] 3. Conclusion...

Embodiment 2

[0034] Example 2 Reverse virtual analysis of compound 1 target protein

[0035] Submit the 4 compounds of formula I to the reverse virtual platform of Beijing Computing Center. The disease target database is composed of the protein structure of human genome druggable genes in the PDB database with complete analysis and partial analysis, and AutoDockVina is used for molecular docking analysis http: / / reversedock.vslead.com / ).

[0036] The compounds are connected to the active site of the target one by one, and the target proteins with the highest scores of the four compounds are all AKR1D1 according to the compound-target interaction energy or pharmacophore matching score.

Embodiment 3

[0037] Example 3 Test to down-regulate AKR1D1 protein level in HepG2 cells

[0038] 1. Experimental samples and experimental methods

[0039] (1) The configuration of the tested sample solution: the test sample is the above compound 1, accurately weigh an appropriate amount of the sample, and use DMSO to configure the solution with the required concentration for the activity test.

[0040] (2) Cell culture

[0041] The HepG2 medium for human liver cancer cells is RPMI 1640 +10%FBS+1% (Penicillin-

[0042] Streptomycin Solution), cultured at 37︒C, 5% carbon dioxide.

[0043] Take HepG2 cells that are in logarithmic growth phase and grow well. They are collected by 0.25% trypsin digestion. The cells are resuspended in RPMI 1640 medium by centrifugation at 12000 rpm for 3 min. The cells are counted on a cell counter, and the cell concentration is diluted with RPMI 1640 medium. 2.5×10 5 cells / ml, connected to a 6-well plate.

[0044] Set up a blank control group without adding any compound,...

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Abstract

The invention discloses an application of a 3-oxo-5 beta-steroid-4-dehydrogenase (5 beta dehydrogenase, EC 1.3.1.3, 3-oxo-5-beta-steroid 4-dehydrogenase, AKR1D1) inhibitor, and belongs to the technical field of medicines. The invention solves the problem of few 5beta dehydrogenase inhibitors in the prior art, and provides an application of a sesterterpene compound as shown in a general formula I or II as a 5beta dehydrogenase inhibitor. In-vitro anti-tumor activity experiments prove that the compound has a proliferation inhibition effect on several tumor cells, the target with the highest score in reverse virtual analysis is the AKR1D1, and the AKR1D1 is reduced in hepatoma carcinoma cells HepG2 by the compound shown in the formula I. Therefore, the compound shown as the general formula Ior II can be used for preparing medicines for resisting liver cancer and treating other AKR1D1 related diseases.

Description

Technical field [0001] The present invention belongs to the technical field of medicine, and specifically relates to a dipterpenoid compound and its use as a 3-oxo-5β-steroid-4-dehydrogenase (5β dehydrogenase, EC 1.3.1.3, 3-oxo-5- Beta-steroid 4-dehydrogenase, AKR1D1) inhibitor application. Background technique [0002] 5β dehydrogenase AKR1D1 is a monomeric soluble protein that belongs to the AKR (aldo-ketoreductase) family (www.med.upenn.edu / akr). The earliest 5β dehydrogenase was purified from rat liver homogenate and was coded as AKR1D2. Using the cDNA of AKR1D2 as a probe, human AKR1D1 was obtained. Since purified AKR1D1 can catalyze the reaction of all Δ4-3-keto steroids including steroid hormones (testosterone, progesterone, glucocorticoids and mineralocorticoids) and bile acid precursors, and the lack of this enzyme not only causes bile acid deficiency , Which also led to the reduction of all human 5β-reduced steroid metabolites, so AKR1D1 is considered the only enzyme...

Claims

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Application Information

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IPC IPC(8): A61K31/122A61P35/00
CPCA61K31/122A61P35/00
Inventor 李枚秋喻力行
Owner 武汉红猎生物科技有限公司
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