Asymmetric Dirhodium-Catalyzed Modification of Immunomodulatory Imide Drugs and Their Biological Assessment.

ABSTRACT: Cereblon (CRBN) has been successfully co-opted to affect the targeted degradation of "undruggable" proteins with immunomodulatory imide drugs (IMiDs). IMiDs act as molecule glues that facilitate ternary complex formation between CRBN and a target protein, leading to ubiquitination and proteasomal degradation. Subtle structural modifications often cause profound and sometimes unpredictable changes in the degradation selectivity. Herein, we successfully utilize enantioselective cyclopropanation and cyclopropenation on intact glutarimides to enable the preparation of stereochemically and regiochemically matched molecular pairs for structure-activity relationship (SAR) analysis across several classical CRBN neosubstrates. The resulting glutarimide analogs were found to reside in unique chemica

SUBMITTER: Tracy WF 

PROVIDER: S-EPMC11403733 | biostudies-literature | 2024 Sep

REPOSITORIES: biostudies-literature