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Diosgenin hydroxamic acid derivatives and their preparation methods and applications

A technology of aglycone hydroxime and derivatives is applied in the field of diosgenin hydroxamic acid derivatives and their preparation, and can solve the problems of low bioavailability, high cytotoxicity, and narrow application range.

Active Publication Date: 2022-04-26
SOUTHWEST UNIVERSITY FOR NATIONALITIES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, as potential antitumor active substances, diosgenin and its derivatives also have disadvantages such as poor water solubility, low bioavailability, high cytotoxicity, and relatively narrow application range, so further structural modification and Pharmacological research to improve its bioavailability and application scope, the invention was created by the special fund for basic scientific research business expenses of Southwest University for Nationalities Central College 2018NQN38

Method used

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  • Diosgenin hydroxamic acid derivatives and their preparation methods and applications
  • Diosgenin hydroxamic acid derivatives and their preparation methods and applications
  • Diosgenin hydroxamic acid derivatives and their preparation methods and applications

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preparation example Construction

[0038] 5. The preparation method of the compound of general formula (I):

[0039]

[0040] Reagents and conditions: (1) DMAP, EDC·HCl, Dicarboxylic acids, CH2Cl2(1a-le) or DMF(lf-1i), r.t., 10h-24h, yield 56-95%.

[0041](2) CDI, NH2OH (50%), CH2Cl2 (2a-2e), r.t., 4h-6h, or. EDC·HCl, HOBt, NH2OTHP, P-TsOH, CH2Cl2 (2f-2i), r.t., 12h-18h , yield 40-87%.

[0042] Synthesis of Compound 1a_1e

[0043] Dissolve diosgenin (1.0g, 2.41mmol) in dichloromethane (30mL), add EDC·HCl (0.55g, 2.90mmol), 4-dimethylaminopyridine (0.354g, 2.90mmol), succinic anhydride (0.97g, 9.96mmol), react at 25°C for 10h, and TLC detects that the reaction is complete. The reaction solution was washed successively with 2N hydrochloric acid (3×10mL), 2N sodium bicarbonate (3×10mL), and water (3×10mL), the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to recover dichloromethane, passed through a silica gel column Chromatography (dichloromethane:methanol (v / v)...

Embodiment

[0062] 1. Synthesis of Compound 1

[0063] Synthesis of Compound 1a

[0064] Diosgenin (1.0g, 2.41mmol, 1eq.) was dissolved in dichloromethane (30mL), and EDC·HCl (0.55g, 2.90mmol, 1.2eq.), 4-dimethylaminopyridine (0.354g, 2.90mmol, 1.2eq.), succinic anhydride (0.97g, 9.96mmol, 4eq), reacted at 25°C for 10h, and TLC detected that the reaction was complete. The reaction solution was washed successively with 2N hydrochloric acid (3×10mL), 2N sodium bicarbonate (3×10mL), and water (3×10mL), the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to recover dichloromethane, passed through a silica gel column Chromatography (dichloromethane:methanol (v / v)=50:1) separated a white solid with a yield of 87%. m.p.222-224℃.1H NMR (400MHz, CDCl3) δ5.36 (d, J = 5.0Hz, 1H, H-6), 4.66-4.58 (m, 1H, H-3), 4.41 (q, J = 7.4Hz,1H,H-16),3.52-3.30(m,2H,H-26),2.70-2.54(m,4H,-COCH2-),2.31(d,J=7.0Hz,2H,H-4 )ppm.13C NMR (100MHz, CDCl3) δ177.36,171.52,139.53,1...

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Abstract

The invention discloses diosgenin hydroxamic acid derivatives and their preparation method and application. Diosgenin is used as a lead compound to prepare a series of hydroxamic acid derivatives through corresponding chemical reactions, and the anti-tumor effect of the derivatives Applications. Pharmacological experiments show that: all synthesized diosgenin hydroxamic acid derivatives are treated with CCK8 method against SW620 (human colon adenocarcinoma cells), H358 (human non-small cell lung cancer cells), HCT‑116 (human colorectal adenocarcinoma cells) and Aspc‑1 (human metastatic pancreatic cancer cells) were tested for antiproliferative activity in vitro. Experimental results show that most of the derivatives have better anti-tumor activity than diosgenin on cells.

Description

technical field [0001] The invention belongs to the field of diosgenin derivatives, and in particular relates to diosgenin hydroxamic acid derivatives and a preparation method and application thereof. Background technique [0002] Cancer is an extremely complex and multifactorial pathological process that can lead to abnormal proliferation of cells. It is a major public health concern and one of the main causes of global morbidity and mortality. Natural products are a good source of medicines with a wide range of pharmaceutical properties, such as antitumor activity. Whether it is naturally occurring, synthetic or semi-synthetic antineoplastic drugs, although a large number of drugs with low cytotoxicity have been developed, effective drugs have not yet been developed for many cancers. High toxicity and chemotherapy resistance are key issues that must be faced in classical anticancer therapy. Therefore, new chemotherapeutic drugs with high activity and good selectivity sho...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J71/00A61P35/00A61K31/58
CPCC07J71/0005A61P35/00
Inventor 肖雪杨鸿均王琳胡越高唐萧萧
Owner SOUTHWEST UNIVERSITY FOR NATIONALITIES
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