Department of Pharmaceutical Sciences , University of Connecticut , 69 North Eagleville Road, Unit 3092 , Storrs , Connecticut 06269 , United States.
Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center , Sanford Burnham Prebys Medical Discovery Institute , 10901 North Torrey Pines Road , La Jolla , California 92037 , United States.
J Med Chem. 2019 Apr 25;62(8):3873-3885. doi: 10.1021/acs.jmedchem.8b01283. Epub 2019 Apr 5.
The Food and Drug Administration-approved antifungal agent, itraconazole (ITZ), has been increasingly studied for its novel biological properties. In particular, ITZ inhibits the hedgehog (Hh) signaling pathway and has the potential to serve as an anticancer chemotherapeutic against several Hh-dependent malignancies. We have extended our studies on ITZ analogues as Hh pathway inhibitors through the design, synthesis, and evaluation of novel des-triazole ITZ analogues that incorporate modifications to the triazolone/side chain region of the scaffold. Our overall results suggest that the triazolone/side chain region can be replaced with various functionalities (hydrazine carboxamides and meta-substituted amides) resulting in improved potency when compared to ITZ. Our studies also indicate that the stereochemical orientation of the dioxolane ring is important for both potent Hh pathway inhibition and compound stability. Finally, our studies suggest that the ITZ scaffold can be successfully modified in terms of functionality and stereochemistry to further improve its anti-Hh potency and physicochemical properties.
美国食品和药物管理局批准的抗真菌药物伊曲康唑（ITZ）因其新的生物学特性而越来越受到研究。特别是，ITZ 抑制刺猬（Hh）信号通路，并有潜力作为几种依赖 Hh 的恶性肿瘤的抗癌化疗药物。我们通过设计、合成和评估新型去三唑 ITZ 类似物，扩展了我们对 Hh 途径抑制剂的研究，这些类似物对支架的三唑酮/侧链区域进行了修饰。我们的总体结果表明，三唑酮/侧链区域可以用各种官能团（肼羧酰胺和间位取代酰胺）代替，与 ITZ 相比，其效力得到提高。我们的研究还表明，二氧戊环环的立体化学取向对 Hh 途径抑制和化合物稳定性都很重要。最后，我们的研究表明，ITZ 支架可以在功能和立体化学方面进行成功修饰，以进一步提高其抗 Hh 效力和物理化学性质。
