Design, Synthesis, and Characterization of Brequinar Conjugates as Probes to Study DHODH Inhibition1. Issue 56 (12th September 2017)

• Record Type: Journal Article
• Authors: Madak, Joseph T.; Cuthbertson, Christine R.; Chen, Wenmin; Showalter, Hollis D.; Neamati, Nouri
• Is Part Of: Chemistry. Volume 23:Issue 56(2017)
• Page Start: 13875
• Page End: 13878
• Publication Date: 2017-09-12
• Subjects: brequinar -- DHODH -- PROTAC -- triphenylphosphonium; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.201702999
• Languages: English
• ISSNs: 0947-6539

Abstract

Abstract: Brequinar, a potent dihydroorotate dehydrogenase (DHODH) inhibitor, has been evaluated in multiple clinical trials as a potential treatment for cancer. To further understand brequinar‐based DHODH inhibition and DHODH′s therapeutic relevance in cancer, we have developed novel brequinar‐based probes. We disclose a 16‐step convergent synthesis of the first brequinar‐PROTAC and a four‐step approach towards the first mitochondrial‐directed brequinar probe. A PROTAC and mitochondria‐directed probe of brequinar both possess cytotoxicity that is superior to brequinar in a colony formation assay. Abstract : Brequin′ news : A novel convergent synthesis of brequinar‐based probes to induce protein degradation (16 steps) and improve mitochondria accumulation (four steps) is disclosed.