期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 59, 期 8, 页码 3635-3649出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.5b01718
关键词
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资金
- National Institutes of Health/National Cancer Institute [CA190617]
- University of Connecticut Research Foundation
- NSF-MRI [CHE-0923449]
Itraconazole (ITZ) is an FDA-approved member of the triazole class of antifungal agents. Two recent drug repurposing screens identified ITZ as a promising anticancer chemotherapeutic that inhibits both the angiogenesis and hedgehog (Hh) signaling pathways. We have synthesized and evaluated first- and second-generation ITZ analogues for their anti-Hh and antiangiogenic activities to probe more fully the structural requirements for these anticancer properties. Our overall results suggest that the triazole functionality is required for ITZ-mediated inhibition of angiogenesis but that it is not essential for inhibition of Hh signaling. The synthesis and evaluation of stereochemically defined des-triazole ITZ analogues also provides key information as to the optimal configuration around the dioxolane ring of the ITZ scaffold. Finally, the results from our studies suggest that two distinct cellular mechanisms of action govern the anticancer properties of the ITZ scaffold.
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