2. Academic Validation
  3. Synthesis and evaluation of novel benzylphthalazine derivatives as hedgehog signaling pathway inhibitors

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

  • Bioorg Med Chem Lett. 2016 Jul 1;26(13):3048-3051. doi: 10.1016/j.bmcl.2016.05.009.
Xiaolong Bao 1,  Yuanqiu Peng 2,  Xiuhong Lu 1,  Jun Yang 2,  Weili Zhao 3,  Wenfu Tan 4,  Xiaochun Dong 5
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, PR China.
  • 2 Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, PR China.
  • 3 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, PR China. Electronic address: [email protected].
  • 4 Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, PR China. Electronic address: [email protected].
  • 5 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, PR China. Electronic address: [email protected].
PMID: 27180012 DOI: 10.1016/j.bmcl.2016.05.009
Abstract

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.

Keywords

Anti-tumor agents; Benzylphthalazines; Hedgehog signaling pathway; Inhibitors.

Figures