Total synthesis of largazole and analogues: HDAC inhibition, antiproliferative activity and metabolic stability

被引：46

作者：

Benelkebir, Hanae ^{[1
]}

Marie, Sabrina ^{[1
]}

Hayden, Annette L. ^{[2
]}

Lyle, Jason ^{[3
]}

Loadman, Paul M. ^{[3
]}

Crabb, Simon J. ^{[2
]}

Packham, Graham ^{[2
]}

Ganesan, A. ^{[1
]}

机构：

[1] Univ Southampton, Sch Chem, Southampton SO17 1BJ, Hants, England

[2] Univ Southampton, Southampton Gen Hosp, Canc Res UK Ctr, Fac Med, Southampton SO16 6YD, Hants, England

[3] Univ Bradford, Inst Canc Therapeut, Bradford BD7 1DP, W Yorkshire, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2011年 / 19卷 / 12期

基金：

英国工程与自然科学研究理事会;

关键词：

Epigenetics; Histone deacetylase; Enzyme inhibitors; Natural products; Depsipeptide; HISTONE DEACETYLASE INHIBITOR; NATURAL-PRODUCTS; SPIRUCHOSTATIN-A; BIOLOGICAL EVALUATION; CLINICAL-TRIALS; DRUG DISCOVERY; FK228; TARGETS; CANCER; ACETYLATION;

D O I：

10.1016/j.bmc.2011.02.024

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The total synthesis of largazole and four analogues is reported. All analogues were nanomolar HDAC inhibitors. The antiproliferative activity is driven by lipophilicity and cell permeability. In murine liver homogenates, largazole is rapidly metabolized (half-life <= 5 min) to the thiol which has a half-life of 51 min. (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：3650 / 3658

页数：9

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