Synthesis of Vismodegib Derivatives as Potential Smo Agonist: A Case of Undergraduate Experimental Teaching

The activation of Hh pathway demonstrates therapeutic potential for many diseases. Smo is the main target for the development of Hh pathway modulators. However, compared with Smo antagonist, the development of Smo agonists is lagging behind. Based on our previous work, a series of vismodegib derivatives were designed and synthesized, and their potential to activate the Hh pathway were evaluated via determining the up-regulation of known pathway target genes Gli1, whcih revealed that many target compounds could activate the Hh pathway. XH-16 and XH-17, with the strongest agonistic effect, could upregulate the expression of Gli1 by more than 50% at a concentration of 10 μM. In vitro cytotoxicity against A549 and the MDA-MB-231 cells was evaluated and the results revealed that XH-16 and XH-17 did not exhibit cytotoxicity at a concentration of 50 μM. Molecular docking results confirmed that XH-16 and XH-17 could bind to Smo indicating that their agonistic effect on the Hh pathway may be due to the activation of Smo. XH-16 and XH-17 with novel molecular scaffold could be used as a lead compound for the development of Smo agonists. Moreover, the research process was introduced in a medicinal chemistry experimental course to assist undergraduates in understanding the core of medicinal chemistry and building capabilities for independently carrying out a medicinal chemistry project. And the teaching practice experiences were summed up to provide suggestions for the development of exploratory experimental course.