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.

A 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 as PowerPoint slide