Benzothiazole meroterpenoid compounds and derivatives thereof, and preparation method and application thereof

A technology for benzothiazole and compound, applied in the field of pharmaceutical compounds, can solve the problems of poor selectivity and high toxicity, and achieve the effects of simple steps, high product purity and good application prospects

Active Publication Date: 2020-12-08
THIRD INST OF OCEANOGRAPHY MINIST OF NATURAL RESOURCES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003]Although many natural ligands of RXRα have been reported, they have poor selectivity and high toxicity

Method used

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  • Benzothiazole meroterpenoid compounds and derivatives thereof, and preparation method and application thereof
  • Benzothiazole meroterpenoid compounds and derivatives thereof, and preparation method and application thereof
  • Benzothiazole meroterpenoid compounds and derivatives thereof, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Example 1. Preparation of benzothiazole heteroterpenoids.

[0033] (1) Cultivate Penicillium allii-sativi (preserved in China Marine Microorganism Culture Collection Management Center, preservation number MCCC 3A00580) on a PDA plate at 25°C for 3 days; then connect the fresh mycelium to 400ml PDB containing After 24 hours, inoculate 10ml of seed solution into 1L Erlenmeyer flasks (100 bottles), each bottle has 80g of oats and 120ml of seawater with a salinity of 3%, and cultured statically for 30 days at 28°C;

[0034] (2) The fermented product obtained in step (1) is extracted three times with ethyl acetate, and the organic solvent is evaporated under reduced pressure to obtain an organic extract (200g); , dichloromethane and methanol were eluted; the dichloromethane layer was concentrated to obtain a crude extract (63.0 g);

[0035] (3) The crude extract obtained in step (2) was separated by normal phase silica gel column chromatography, and gradient elution was per...

Embodiment 2

[0044] Example 2. Detection of RXRα dual reporter gene activity: Detect whether the compound can affect the transcriptional activity of RXRα, and preliminarily explore whether the compound may have a binding effect on RXRα.

[0045] In this example, a dual-luciferase reporter (DLR) detection system composed of firefly luciferase (Firefly luciferase, FL) reporter gene and Renilla luciferase (Rellina luciferase, RL) reporter gene was used. . The RL reporter gene was used as an internal control to normalize the measurements of the FL reporter gene. In cells lacking endogenous RXRα and its downstream signaling components, receptor RXRα and a reporter gene containing RXRα response elements are introduced by transfection, thereby simply simulating the transcriptional activation process of receptors in vivo.

[0046] This embodiment sets the following 3 groups:

[0047] Negative control group: equal amount of culture medium, 0.1% DMSO, containing cells, without adding compounds of ...

Embodiment 3

[0056] Example 3. Biacore experiment: evaluating whether compounds I-III bind directly to RXRα-LBD protein.

[0057] First, the purified nuclear receptor RXRα-LBD protein was coupled to Biacore's CM5 chip. Then the compounds to be tested were diluted with PBS to make solutions with different concentrations and then injected. When the sample to be measured flows over the surface of the chip, the combination of biomolecules causes the increase of the surface mass of the biosensor, resulting in a change in the refractive index. By monitoring the angle change of SPR, the kinetic binding and dissociation constants of the analyte can be automatically obtained. affinity and specificity etc. The BiacoreT200 detector can detect the interaction between the target protein and the sample in real time, and the binding strength is expressed in units of RU (response units, RU) (a change in the concentration of binding substances on the chip surface by 1pg / mm2 is defined as 1RU). We used Bi...

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Abstract

The invention relates to a benzothiazole meroterpenoid compound derived from deep sea fungi and a derivative, a preparation method and application thereof in antitumor drugs. The benzothiazole meroterpenoid compound is a compound shown as formulas I to III or salts thereof. The compound is separated from a fermentation product of Penicillium allii-sativi and inhibits the transcriptional activity of RXRalpha by combining with an anti-tumor target RXRalpha so as to achieve a remarkable anti-tumor effect. The compound can be used for preparing, researching and developing anti-cancer drugs, and has a good application prospect.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical compounds, in particular to a benzothiazole heteroterpenoid compound and its derivatives as well as a preparation method and application thereof. Background technique [0002] Tumor is one of the diseases that seriously threaten human health today. Nuclear receptors are a class of ligand-dependent transcriptional regulators, distributed in the cytoplasm and nucleus of cells, and play an important role in maintaining the homeostasis of the body. Retinol X receptor (RXR) is an important member of the nuclear receptor family, and is considered to be the core member with the most development prospects. It plays a role in regulating the proliferation of various cancer cells such as lung cancer, breast cancer, liver cancer and prostate cancer. play an important role in apoptosis. RXRα contains an N-terminal region, a DNA-binding domain and a ligand-binding domain (LBD). RXRα-LBD has a Ligand B...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/68C07D277/62A61P35/00C12P17/14C12R1/80
CPCC07D277/68C07D277/62A61P35/00C12P17/14
Inventor 杨献文谢春兰鄢庆祥邹正彪何志辉
Owner THIRD INST OF OCEANOGRAPHY MINIST OF NATURAL RESOURCES
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