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

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.