Fat synthetase inhibitor and applications thereof

A technology of fatty acid synthase and compound, which is applied in the field of medicine and biology, can solve the problems of tumor cell apoptosis and unclear tumor mechanism, and achieve the effect of promoting tumor cell apoptosis, important clinical application prospects, and inhibiting tumor cell proliferation

Active Publication Date: 2019-10-22
无锡代达康健生物医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the mechanism of FASN regulating tumors is not yet clear. Some researchers believe that the inhibition of FASN reduces the supply of structural lipids and energy required for cell proliferation, which is the cause of tumor cell apoptosis.

Method used

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  • Fat synthetase inhibitor and applications thereof
  • Fat synthetase inhibitor and applications thereof
  • Fat synthetase inhibitor and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] The synthesis of embodiment 1 formula I-1 compound

[0045]

[0046] The specific synthesis method is as follows:

[0047] (1) Synthesis of intermediate 1 compound 5-(4-bromophenylamino)-5-oxopentanoic acid:

[0048] Add 5-ethoxy-5-oxopentanoic acid (2g, 12.5mM) to a 100mL single-necked bottle, and dichloromethane (30mL), cool to 0°C in an ice bath, and slowly add thionyl chloride (3g, 25mM). After reaching room temperature, heat to reflux. The reaction solution was quenched and spin-dried to obtain 1 g of intermediate 1 product with a yield of 44.9%;

[0049] (2) Synthesis of intermediate 2 compound 5-(4-bromophenylamino)-5-carbonylpentanoic acid ethyl ester:

[0050] Add p-bromoaniline (1.15g, 6.7mmol), dichloromethane (15mL), and triethylamine (0.85g, 8.4mmol) to a 100mL single-necked bottle, cool down to 0°C, and slowly add intermediate 1 (1g, 5.6mmol) at room temperature and stirred overnight, TLC showed that the reaction was complete, the reaction solution ...

Embodiment 2

[0056] The synthesis of embodiment 2 formula I-2 compound

[0057]

[0058] (1) Synthesis of 4-((tert-butoxycarbonyl) amino) butanoic acid:

[0059] Add 4-aminobutyric acid (2g, 19.4mmol, 1.0eq), THF (15mL), water (15mL), sodium hydroxide (1.6g, 38.8mmol) into a 100mL single-necked bottle, cool to 0°C, and slowly drop Plus (Boc) 2 O (5.1g, 23.3mmol), stirred at 25°C for 12hrs after dropping. After the reaction was complete, THF was removed by rotary evaporation, 15 mL of water was added, and excess (Boc) was extracted by ethyl acetate (10 mL). 2 O, the aqueous phase was adjusted to pH 2-3 with citric acid or hydrochloric acid, extracted with ethyl acetate (15 mL), and the organic phase was dried with anhydrous sodium sulfate and spin-dried to obtain 3.5 g of product with a yield of 88%.

[0060] (2) Synthesis of N-(4-bromophenyl)-4-((tert-butoxycarbonyl)amino)butanamide:

[0061] Add p-bromoaniline (1g, 5.8mmol), dichloromethane (15mL), and triethylamine (0.76g, 7.4mmol...

Embodiment 3

[0067] The synthesis of embodiment 3 formula I-3 compound

[0068] The structure of compound 1-3 is shown below:

[0069]

[0070] Dissolve I-2 compound (0.6mmol) in dichloromethane (5mL), cool to -20°C, slowly add BBr 3 (0.9 mmol). It was then stirred at room temperature for 3 hours. TLC showed the reaction was complete. Add water (15mL) to quench, DCM (15mL) to extract, after the organic phase is dried, the organic phase is dried with anhydrous sodium sulfate, filters, after spin-drying, obtain crude product, silica gel column chromatography (petroleum ether:ethyl acetate=100:1 to 3:1) to obtain 200 mg of I-3 compound with a yield of 69%.

[0071] 1 H-NMR (DMSO, 400MHz) δ: 1.65(m,2H), 2.31(t,2H), 3.05(t,2H), 4.13(d,2H), 6.22(t,1H), 6.46(t,1H ), 6.74(t,1H), 7.20(m,2H), 7.52(m,2H), 7.60(m,2H), 10.05(s,1H), 10.12(s,1H). Mass spectrum (MS+): 485,487, m / z: [M+2, M+4].

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Abstract

The invention discloses a fat synthetase inhibitor and applications thereof, and belongs to the technical field of medical biology. The inhibitor can significantly inhibit the activity of fatty acid synthetase without affecting normal expression, and can also adjusting the proportion of fatty acid in cells; the inhibitor has good tumor proliferation inhibition effects, and can make the growth period of tumor cells stagnate in interphase, prevent the tumor cells from splitting, inhibit the proliferation of the tumor cells, promote the apoptosis of the tumor cells and achieve treatment effects on tumor; and the inhibitor can be used for drugs for treating tumor and metabolic related diseases, so that the inhibitor has important clinical application prospects.

Description

technical field [0001] The invention belongs to the technical field of medicine and biology, and in particular relates to a liposynthase inhibitor and its application. Background technique [0002] Fatty acids in the human body are directly derived from exogenous fatty acids ingested from the outside world on the one hand, and endogenous fatty acids synthesized by the body itself on the other hand. Fatty acid synthase (FASN) is a key enzyme in the process of endogenous fatty acid synthesis in organisms. It generates long-chain fatty acids by catalyzing acetyl-CoA and malonyl-CoA. FASN includes acetyltransferase (AT), malonyltransferase (MT), β-ketoacyl synthase (KS), β-ketoacyl reductase (KR), β-hydroxyacyl dehydratase (HD ), enoyl reductase (ER) and thioesterase (TE), which can be divided into two subtypes, type I and type II. FASN in bacteria and plants belongs to type II, which is a multi-enzyme system composed of the above seven functional domains as independent enzyme...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/167A61K31/17A61P35/00A61P37/02A61P3/04A61P3/06A61P11/00A61P9/12A61P9/00A61P1/00A61P3/10A61P13/12A61P9/10A61P31/12A61P35/02A61P29/00A61P19/02A61P19/08A61P17/06A61P11/06A61P37/06
CPCA61K31/167A61K31/17A61P35/00A61P37/02A61P3/04A61P3/06A61P11/00A61P9/12A61P9/00A61P1/00A61P3/10A61P13/12A61P9/10A61P31/12A61P35/02A61P29/00A61P19/02A61P19/08A61P17/06A61P11/06A61P37/06
Inventor 陈永泉渠宏雁唐春雷崔国祯吴国胜冯宁翰王小英单锴朱升龙韦冷云
Owner 无锡代达康健生物医药科技有限公司
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