Deuterium Editing of Small Molecules: A Case Study on Antitumor Activity of 1,4-Benzodiazepine-2,5-dione Derivatives,Journal of Medicinal Chemistry

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Deuterium Editing of Small Molecules: A Case Study on Antitumor Activity of 1,4-Benzodiazepine-2,5-dione Derivatives
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-07-18 , DOI: 10.1021/acs.jmedchem.4c00796
Wenjun Yu ₁ , Shiping Fang ₂ , Xilei Xie ₂ , Wenwu Liu ₂ , Xinhua Liu ₂ , Yanan Du ₃ , Purong Zheng ₁ , Gang Liu ₂

Affiliation

Substituting hydrogen with deuterium in drug molecules is an appealing bioisosteric strategy for the generation of novel chemical entities in drug development. Optimizing lead compounds through deuteration has proven to be challenging and unpredictable, particularly for compounds with multiple metabolic sites. This study presents the pioneering achievement of substituting up to 19 hydrogen atoms with deuterium on 1,4-benzodiazepine-2,5-dione derivatives, shedding light on the structure–metabolism relationship and the impact of multiple deuterations on drug-like properties. Notably, the deuterated compound 3f exhibited remarkable antitumor activity in vivo and demonstrated favorable drug-like properties as a drug candidate.

中文翻译：

小分子氘编辑：1,4-苯二氮卓-2,5-二酮衍生物抗肿瘤活性案例研究

在药物分子中用氘取代氢是药物开发中生成新型化学实体的一种有吸引力的生物电子等排策略。事实证明，通过氘化优化先导化合物具有挑战性且不可预测，特别是对于具有多个代谢位点的化合物。这项研究提出了用氘取代 1,4-苯二氮卓-2,5-二酮衍生物上多达 19 个氢原子的开创性成就，揭示了结构-代谢关系以及多次氘化对药物样特性的影响。值得注意的是，氘代化合物3f在体内表现出显着的抗肿瘤活性，并作为候选药物表现出良好的类药特性。

更新日期：2024-07-18

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