Use of compound with structure similia combretastatin A4 in preparation medicine for inhibiting tubulin polymerization or treating tumor

An anti-tumor drug and a technology with a similar structure, which can be applied in the direction of anti-tumor drugs, drug combinations, ether/acetal active ingredients, etc., can solve the problems of poor efficacy of deep tumors and achieve broad application prospects

Inactive Publication Date: 2007-11-21
SUN YAT SEN UNIV
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  • Summary
  • Abstract
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  • Claims
  • Application Information

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Problems solved by technology

However, the mechanism and characteristics of VDA drugs are just complementary to traditional chemoradiotherapy (traditional chemoradiotherapy has a strong killing effect on peripheral tumor cells with sufficient oxygen supply, but has a poor effect on deep tumors). Therefore, VDA drugs are suitable for use with other drugs. Combination of treatment modalities, which is also reflected in ongoing clinical research

Method used

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  • Use of compound with structure similia combretastatin A4 in preparation medicine for inhibiting tubulin polymerization or treating tumor
  • Use of compound with structure similia combretastatin A4 in preparation medicine for inhibiting tubulin polymerization or treating tumor
  • Use of compound with structure similia combretastatin A4 in preparation medicine for inhibiting tubulin polymerization or treating tumor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Embodiment 1: In vitro anti-tumor cell proliferation experiment of Combretastatin A4 analogs

[0021] The selected cell lines include: human oral epithelial carcinoma KB-3-1, human gastric adenocarcinoma MGC803, cervical carcinoma HeLa, breast carcinoma MCF-7, liver carcinoma HepG 2 , colon cancer LoVo and leukemia HL-60 cell lines, etc. The tumor cells in the logarithmic growth phase were taken to make a certain concentration of cell suspension and inoculated in a 96-well plate. A certain concentration of the drug to be tested was added to each well, and no drug was added to the control well. Four parallel wells were set for each concentration. After culturing for 68 hours, add MTT 100 μg / well, continue culturing for 4 hours, discard the culture medium, add 200 μL dimethyl sulfoxide, shake for 15 minutes to dissolve completely, measure the 570 / 630 nm dual-wavelength absorbance with a microplate reader, and use Logit The drug concentration at which 50% of the cell grow...

Embodiment 2

[0025] Example 2: Combretastatin A4 analogue M410 inhibits tubulin polymerization activity in vitro

[0026] Tubulin solution is a colorless and transparent solution at 0-4°C. When kept warm at 37°C, tubulin polymerizes into microtubules, and the absorbance (OD value) of the solution at 340nm rises and reaches a plateau within a certain period of time. According to the measured OD value plotted against the holding time, a characteristic "S" type polymerization curve can be drawn. Drugs that interfere with microtubule polymerization can alter the shape of the curve, and consequently the plateau.

[0027] Dissolve the purified bovine brain tubulin powder into a 10mg / mL stock solution with General Tubulin Buffer and place in an ice bath; dilute the tubulin stock solution to 2mg / mL with General Tubulin Buffer, add GTP to 1mM, add glycerol to 10 %, quickly add this mixed solution into the pre-cooled cuvette on ice, and adjust the zero point at 340nm of the ultraviolet spectrophoto...

Embodiment 3

[0028] Embodiment 3: Combretastatin A4 analog M410 inhibits human colon cancer (LoVo) growth experiment in nude mice

[0029] Take 1×10 LoVo cells in the logarithmic growth phase 7 / mL was inoculated in the right armpit of nude mice, 0.2 mL per mouse. Once the tumor grows to 200-300mm 3, and the mice were randomly divided into 5 groups according to tumor size. Group 1 is normal saline control group, group 2 is CA4P group (25mg / kg), group 3 is DDP group (1mg / kg), group 4 is M410 group (25mg / kg), group 5 is DDP (1mg / kg) combined with M410 (25mg / kg) (1 hour after M410 was used in DDP). Intraperitoneal administration once every 3 to 4 days, a total of 4 times. Every 3 to 4 days, the tumor size was measured with a vernier and the body weight of the mice was weighed. The tumor volume (Tumor Volume, mm 3 ) is calculated according to (L×S×S) / 2, where L (mm) represents the long diameter of the tumor, and S (mm) represents the short diameter of the tumor. The mice were sacrificed ...

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Abstract

The invention is concerned with the compositions that the structure is similar with Combretastatin A4 and using for depression tubulin polymerization or anti-tumor drug.

Description

technical field [0001] The present invention relates to a compound with a structure similar to Combretastatin A4, and specifically relates to the application of the compound with a structure similar to Combretastatin A4 in the preparation of drugs for inhibiting tubulin polymerization or antitumor. Background technique [0002] Vascular Disrupting Agents (VDA) are an important new force in the field of anti-vascular and anti-tumor drugs that have emerged in recent years. Vasoblocking agents (VDAs) are mechanistically derived from tubulin binding and belong to anti-microtubule drugs. Studies suggest that there are three relatively clear small molecule binding sites in the molecular structure of tubulin, namely colchicine binding site (Colchicine domain), vinblastine binding site (Vinca domain) and taxane binding site (Taxane site). Both localize to tubulin before polymerization, and the latter localize to microtubules after polymerization. Ligands that bind to colchicine an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/09A61K31/661A61P35/00
Inventor 冼励坚邹永蔡于琛王志新
Owner SUN YAT SEN UNIV
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