(2-氨基磺酰基吡啶-6-酰基)吡唑嘧啶衍生物作为Wee1肿瘤抑制剂的合成及生物学评价

IF 1.7 4区 化学
Yeon Ju Kim, Myoung Eun Jung, Ju Yeong Lee, Yun-Han Lee, Gildon Choi, Moon-Kook Jeon
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引用次数: 0

摘要

为了设计一种基于类似物的新型Wee1抑制剂,我们分析了adavosertib的体外ADMET和体内PK特性。基于adavosertib的特性,我们设计了一种新的靶向化合物1a,以氨基磺酰基取代adavosertib中的2-羟基丙烷-2-基部分,以提高其代谢稳定性。合成了目标化合物1a的衍生物,并对Wee1酶抑制和肝微粒体I期稳定性进行了评价。我们确定化合物1a为亚纳摩尔Wee1抑制剂,另外10个化合物具有一位数纳摩尔Wee1抑制活性,其中包括1a在内的7个化合物与adavosertib相比表现出更好的代谢稳定性。然而,所有合成化合物的MDA-MB-231细胞生长抑制活性和选定化合物的Wee1底物磷酸化抑制活性总体上不如阿avosertib。此外,具有代表性的化合物1a表现出低通透性,这可能是化合物1a细胞活性低的原因。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Synthesis and biological evaluation of (2-aminosulfonylpyridin-6-yl)pyrazolopyrimidinone derivatives as Wee1 inhibitors for cancer treatment

Synthesis and biological evaluation of (2-aminosulfonylpyridin-6-yl)pyrazolopyrimidinone derivatives as Wee1 inhibitors for cancer treatment

Synthesis and biological evaluation of (2-aminosulfonylpyridin-6-yl)pyrazolopyrimidinone derivatives as Wee1 inhibitors for cancer treatment

For an analog-based design of novel Wee1 inhibitors, we profiled in vitro ADMET and in vivo PK properties of adavosertib. Based on the properties of adavosertib, we aimed to improve its metabolic stability by designing a novel target compound 1a with an aminosulfonyl group instead of the 2-hydroxypropan-2-yl moiety in adavosertib. Derivatives of target compound 1a were synthesized and evaluated for Wee1 enzyme inhibition and liver microsomal phase I stability. We identified compound 1a as a sub-nanomolar Wee1 inhibitor and 10 additional compounds with one-digit nanomolar Wee1 inhibitory activity, among which seven compounds including 1a exhibited improved metabolic stabilities compared with adavosertib. However, MDA-MB-231 cell growth inhibitory activities of all synthesized compounds and Wee1 substrate phosphorylation inhibitory activities of selected compounds were inferior to adavosertib overall. Moreover, the representative compound 1a exhibited low permeability, which may be the reason for the low cellular activities of compound 1a.

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来源期刊
Bulletin of the Korean Chemical Society
Bulletin of the Korean Chemical Society Chemistry-General Chemistry
自引率
23.50%
发文量
182
期刊介绍: The Bulletin of the Korean Chemical Society is an official research journal of the Korean Chemical Society. It was founded in 1980 and reaches out to the chemical community worldwide. It is strictly peer-reviewed and welcomes Accounts, Communications, Articles, and Notes written in English. The scope of the journal covers all major areas of chemistry: analytical chemistry, electrochemistry, industrial chemistry, inorganic chemistry, life-science chemistry, macromolecular chemistry, organic synthesis, non-synthetic organic chemistry, physical chemistry, and materials chemistry.
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