Pace Jennifer R, DeBerardinis Albert M, Sail Vibhavari, Tacheva-Grigorova Silvia K, Chan Kelly A, Tran Raymond, Raccuia Daniel S, Wechsler-Reya Robert J, Hadden M Kyle
Department of Pharmaceutical Sciences, University of Connecticut , 69 North Eagleville Road, Unit 3092, Storrs, Connecticut 06269-3092, United States.
Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute , 2880 Torrey Pines Scenic Drive, La Jolla, California 92037, United States.
J Med Chem. 2016 Apr 28;59(8):3635-49. doi: 10.1021/acs.jmedchem.5b01718. Epub 2016 Apr 6.
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.
伊曲康唑（ITZ）是一种经美国食品药品监督管理局（FDA）批准的三唑类抗真菌药物。最近的两项药物重新利用筛选将ITZ鉴定为一种有前景的抗癌化疗药物，它能抑制血管生成和刺猬（Hh）信号通路。我们已经合成并评估了第一代和第二代ITZ类似物的抗Hh和抗血管生成活性，以更全面地探究这些抗癌特性的结构要求。我们的总体结果表明，三唑官能团是ITZ介导的血管生成抑制所必需的，但对于Hh信号抑制并非必不可少。立体化学定义的去三唑ITZ类似物的合成和评估也提供了关于ITZ支架二氧戊环周围最佳构型的关键信息。最后，我们的研究结果表明，两种不同的细胞作用机制决定了ITZ支架的抗癌特性。
