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- Title
Design, Synthesis, and Characterization of Brequinar Conjugates as Probes to Study DHODH Inhibition.
- Authors
Madak, Joseph T.; Cuthbertson, Christine R.; Chen, Wenmin; Showalter, Hollis D.; Neamati, Nouri
- 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.
- Subjects
CHEMICAL synthesis; DIHYDROOROTATE dehydrogenase; CLINICAL trials; CANCER treatment; CELL-mediated cytotoxicity
- Publication
Chemistry - A European Journal, 2017, Vol 23, Issue 56, p13875
- ISSN
0947-6539
- Publication type
Article
- DOI
10.1002/chem.201702999