Difluoro-substituted romidepsin analogue as well as preparation method and application thereof

A technology of romidepsin and analogues, applied in the field of chemical pharmaceuticals, can solve problems such as lack of high selectivity or specificity

Pending Publication Date: 2022-04-22
FUDAN UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Since the effects of each HDAC isomerase on the occurrence and development of tumor cells have not been fully elucidated, and there is a lack of highly selective or specific HDAC inhibitor molecular tools, the development of type I selective HDAC in...

Method used

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  • Difluoro-substituted romidepsin analogue as well as preparation method and application thereof
  • Difluoro-substituted romidepsin analogue as well as preparation method and application thereof
  • Difluoro-substituted romidepsin analogue as well as preparation method and application thereof

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Experimental program
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Embodiment 1

[0078] Synthesis of Romidepsin Difluoro Substituted Analog 10

[0079] Step a:

[0080]

[0081] Take a clean and dry 100mL eggplant-shaped reaction bottle, protect it with argon, add raw materials aldehyde 1 (2.59g, 7.23mmol), R-sulfinamide (1.23g, 10.1mmol) and KHSO 4 (1.18g, 8.7mmol), dissolved in 40mL of anhydrous toluene, reacted at 45°C for 1h, then stopped the reaction, filtered off KHSO 4, concentrated, and purified by silica gel column chromatography (elution condition: PE / EA=10:1) to obtain 2.82 g of a colorless viscous solid with a yield of 85%.R f =0.2(PE / EA=10:1) -159.9 (c=1.9CHCl3). 1 H NMR (400MHz, CDCl 3 )δ8.11–8.09(m,1H),7.48–7.09(m,15H),6.47–6.15(m,2H),2.35–2.20(m,4H),1.19(s,9H). 13 C NMR (151MHz, CDCl 3 )δ163.81,148.63,144.65,129.53,127.92,126.71,66.90,61.17,57.24,48.53,32.05,30.40,28.12,24.72,22.43.ESI-MS(m / z):484.2[M+Na] + .HRMS-ESI(m / z):[M+Na] + Calcd. For C 28 h 31 NOS 2 Na:484.1739,found:484.1744;

[0082] Step b:

[0083]

[0084] T...

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Abstract

The invention belongs to the technical field of chemical pharmacy, and relates to a difluoro-substituted romidepsin analogue, a preparation method thereof and application of the analogue as an antitumor agent.According to the difluoro-substituted romidepsin analogue, a compound 1 reacts with optically pure tert-butyl sulfinamide to obtain a compound 2, and an organic zinc reagent reacts with the compound 2 chemically to generate a compound 3; carrying out ester hydrolysis to obtain a compound 4; reacting the compound 4 with an intermediate to obtain a compound 5; performing deprotection reaction on the compound 5 to obtain a compound 6 containing free amino groups; carrying out ester hydrolysis on the compound 6 to obtain a compound 7 containing free carboxyl; carrying out intramolecular condensation reaction on the compound 7 and an intermediate to prepare a compound 8; the compound 8 is subjected to a protection group removal reaction and intramolecular disulfide bond generation, and a compound 9 is prepared. The compound disclosed by the invention has a strong effect of inhibiting various tumor cells, and particularly can inhibit cell proliferation of gastric cancer, bladder cancer, colon cancer, liver cancer, lymph cancer or breast cancer, so that the compound has potential anti-tumor application.

Description

technical field [0001] The invention belongs to the technical field of chemical pharmacy, and relates to a difluoro-substituted romidepsin analogue, its preparation method and application, in particular to a new difluoro-substituted romidepsin analogue, its preparation method and Use of the compound medicine or its composition as an antitumor therapeutic agent. Background technique [0002] The prior art discloses that cancer has become another major disease that endangers human health after cardiovascular and cerebrovascular diseases. According to statistics, since the 1970s, the number of cancer incidence and death in my country has been on the rise. It is expected that by 2020 The annual incidence of tumors will be as high as 3 million, and the annual death toll will reach 2.5 million. Cancer has become the leading cause of death among urban residents in my country. Therefore, research and discovery of low-toxicity and high-efficiency tumor treatment drugs are of great com...

Claims

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Application Information

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IPC IPC(8): C07K5/103C07K1/06A61K38/07A61P35/00
CPCC07K5/101A61P35/00A61K38/00
Inventor 雷新胜张冰冰刘晴
Owner FUDAN UNIV
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