Design, synthesis, and biological evaluation of hypoxic-activation prodrug TH-302 derivatives

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-03-17 DOI:10.1016/j.bmcl.2025.130189

Zhengyi Li , Xingchen Yang , Shun Wang , Hongzhao Ma , Ke Yang , Jing Shi , Xin Wang

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Abstract

This study aims to design and develop novel and efficient anti-hypoxic cell tumor drugs. Using the TH-302 as lead compound, structural modifications are conducted to synthesize a series of novel derivatives to investigate the structural activity relationship (SAR) against ovarian cancer cell line (SKOV3) and glioblastoma cell line (U87MG) in vitro. The structural modifications mainly include four aspects: changes in substituents on N; changes in isomers; changes in nitro group position; changes in substituting halogens in phosphoramide mustard. The results of CCK-8 assay indicate that the steric hindrance and electronic effects of substituents on N have significant impacts on the activity, while changes in nitro group positions have minimal effects on the activity, and Bromo-phosphoramide mustard exhibits better activity than Chloro-phosphoramide mustard. Compounds 15c and 16d exhibit significantly superior antitumor activity compared to TH-302, with IC₅₀ values of 42 μM and 32 μM for SKOV3 cells, and IC₅₀ values of 47 μM and 41 μM for U87MG cells, respectively.

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低氧活化前药TH-302衍生物的设计、合成和生物学评价。

本研究旨在设计和开发新型、高效的抗缺氧细胞肿瘤药物。以TH-302为先导化合物，进行结构修饰，合成一系列新型衍生物，在体外研究其对卵巢癌细胞系SKOV3和胶质母细胞瘤细胞系U87MG的结构活性关系（SAR）。结构修饰主要包括四个方面：N上取代基的改变；异构体的变化；硝基位置的变化；磷酰胺芥中卤素取代的变化。CCK-8测定结果表明，取代基对N的位阻和电子效应对活性有显著影响，而硝基位置的变化对活性影响较小，溴磷酰胺芥菜的活性优于氯磷酰胺芥菜。化合物15c和16d的抗肿瘤活性明显优于TH-302，对SKOV3细胞的IC50值分别为42 μM和32 μM，对U87MG细胞的IC50值分别为47 μM和41 μM。

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来源期刊

Bioorganic & Medicinal Chemistry Letters 医学-医药化学

CiteScore

5.70

自引率

3.70%

发文量

463

审稿时长

27 days

期刊介绍： Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.