Deuterium Editing\nof Small Molecules: A Case Study\non Antitumor Activity of 1,4-Benzodiazepine-2,5-dione Derivatives

Substituting\nhydrogen with deuterium in drug molecules is an appealing\nbioisosteric strategy for the generation of novel chemical entities\nin drug development. Optimizing lead compounds through deuteration\nhas proven to be challenging and unpredictable, particularly for compounds\nwith multiple metabolic sites. This study presents the pioneering\nachievement of substituting up to 19 hydrogen atoms with deuterium\non 1,4-benzodiazepine-2,5-dione derivatives, shedding light on the\nstructure–metabolism relationship and the impact of multiple\ndeuterations on drug-like properties. Notably, the deuterated compound <b>3f</b> exhibited remarkable antitumor activity <i>in vivo</i> and demonstrated favorable drug-like properties as a drug candidate.