Design, Synthesis, and Characterization of Brequinar Conjugates as Probes to Study DHODH Inhibition

作者：Madak Joseph T; Cuthbertson Christine R; Chen Wenmin; Showalter Hollis D^*; Neamati Nouri^*

来源：Chemistry - A European Journal, 2017, 23(56): 13875-13878.

DOI：10.1002/chem.201702999

• brequinar
• DHODH
• PROTAC
• triphenylphosphonium

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 DHODHs 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.

• 出版日期2017-10-9