Synthesis and evaluation of novel benzylphthalazine derivatives as hedgehog signaling pathway inhibitors

We report herein the design and synthesis of a series of novel benzylphthalazine derivatives as hedgehog signaling pathway inhibitors. Gli-luciferase assay demonstrated that changing piperazine ring of Anta XV to different four, five or six-membered heterocyclic building blocks afforded significant influences on Hh pathway inhibition. In particular, compound 10e with piperidin-4-amine moiety was found to possess 12-fold higher Hh inhibitory activities comparing to the lead compound in vitro. In vivo efficacy of 10e in a ptch+/−p53−/− mouse medulloblastoma allograft model also indicated encouraging results.

Graphical abstractA series of novel benzylphthalazine derivatives were prepared and their in vitro hedgehog signaling pathway inhibitory activities as well as in vivo antitumor potency were reported.Figure optionsDownload full-size imageDownload as PowerPoint slide