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Colchicine derivative as well as preparation method and application thereof

A technology for colchicine and derivatives, which is applied in the field of colchicine derivatives and their preparation, can solve the problems of high cytotoxicity, achieve the effects of reducing cytotoxicity, maintaining anti-tumor activity, and broad application prospects

Active Publication Date: 2015-05-27
上海中科润达精准医学检验有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Aiming at solving the technical problem that colchicine-like drugs are highly toxic to cells in the prior art

Method used

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  • Colchicine derivative as well as preparation method and application thereof
  • Colchicine derivative as well as preparation method and application thereof
  • Colchicine derivative as well as preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Embodiment 1: the synthesis of structural formula (Ia-1) compound

[0032]

[0033] The synthetic route is as follows:

[0034]

[0035] Concrete synthetic steps are as follows:

[0036] To a solution of colchicine compound 1a (1 g, 2.6 mmol) in 10 mL of acetonitrile was sequentially added di-tert-butyl dicarbonate (2.3 g, 10.4 mmol), 4-dimethylaminopyridine (0.64 g, 5.2 mmol) and triethylamine (1.5mL, 10.4mmol), reflux for 4 hours. Add water to quench the reaction, first spin out most of the acetonitrile and then extract with ethyl acetate, the organic phase is sequentially washed with 1M HCl, saturated NaHCO 3 solution and washed with water, anhydrous Na 2 SO 4 After drying, column (dichloromethane / acetonitrile=4:1) gave the product 2a as a yellow solid (0.89 g, 68% isolated yield).

[0037] Sodium methoxide (200 mg, 3.6 mmol) was added to a solution of compound 2a (0.89 g, 1.8 mmol) in 10 mL of methanol, and reacted at room temperature for 0.5 hours. Add ...

Embodiment 2

[0040] Embodiment 2: the synthesis of structural formula (Ib-1) compound

[0041]

[0042] The synthetic route is as follows:

[0043]

[0044] Compound 4a (100 mg, 0.28 mmol) and compound 5b (124 mg, 0.34 mmol) were dissolved in 5 mL of N-methylpyrrolidone, then triethylamine (80 μL, 0.56 mmol) was added, and heated to 100°C for 1 hour. After cooling to room temperature, ethyl acetate was added, and H 2 O washed, anhydrous Na 2 SO 4 After drying, column (dichloromethane / methanol=20:1) gave product 6b (145 mg, 89% isolated yield) as a yellow solid.

[0045] Will K 2 CO 3 (345 mg, 2.5 mmol) in 1 mL of aqueous solution was added to compound 6b (145 mg, 0.25 mmol) in 3 mL of methanol solution, and reacted at room temperature for 0.5 hours. First spin out most of the methanol and then extract with dichloromethane, anhydrous Na 2 SO 4 After drying, compound 7b was spin-dried to obtain compound 7b, which was used directly without further purification because compound 7b ...

Embodiment 3

[0047] Embodiment 3: biological activity test

[0048] Test method: Add cells to a 96-well plate, about 10,000 cells per well, at 37 degrees, 5% CO 2 Adhere to the wall overnight under environmental conditions, remove the medium, and add fresh medium containing different concentrations of compounds. After 48 hours of incubation, MTS reagent (Promega) was added and read (490 nm, Perkin-Elmer Envision) two hours later.

[0049] Activity data:

[0050] The activity of colchicine and its derivatives on cancer cells and the toxicity test on normal cells are expressed by IC50 (nM) values, and the data results are shown in Table 1.

[0051] Table 1, IC50 values ​​of colchicine and its derivatives on cancer cells and normal cells

[0052] compound

SKBR3

HEK293

3T3-L1

A

B

Ia-1

12.18

24

146.8

0.59

12.05

Ib-1

17.86

67.2

231.4

0.93

12.96

Compound 4a

37.94

64.58

81.84

0.59

2.16 ...

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Abstract

The invention belongs to the field of anticancer drugs and particularly relates to a colchicine derivative as well as a preparation method and application thereof in preparation of drugs for treating cancers. According to the preparation method, colchicine is introduced with a vinyl sulfamide group to obtain the colchicine derivative; the colchicine derivative has the effects of retaining the antineoplastic activity and remarkably reducing cytotoxicity, so the colchicine derivative has wide application prospect in preparation of anticancer drugs.

Description

technical field [0001] The invention belongs to the field of drugs with anticancer activity, and specifically relates to colchicine derivatives and their preparation methods and applications. Background technique [0002] Colchicine (colchicine) is a tricyclic alkaloid extracted from colchicine, a plant of the Liliaceae family, and is currently mainly used for the treatment of acute gout. Colchicine also has anti-tumor activity and is one of the earliest known tubulin polymerization inhibitors. Its mechanism is similar to paclitaxel, that is, it binds to tubulin dimers, prevents tubulin conversion, and stops cells at Metaphase of mitosis, resulting in cell death. The success of paclitaxel has brought colchicine attention again, because colchicine has better water solubility and is cheaper. However, the toxicity of colchicine is comparable to its activity, so it has not been applied in the field of anti-cancer so far. Existing research results do not maintain activity whil...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C311/11C07C303/38A61K31/18A61P35/00
CPCY02P20/55
Inventor 姜标曹刚杨建平
Owner 上海中科润达精准医学检验有限公司
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