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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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.