2. Academic Validation
  3. Meeting organometallic chemistry with drug discovery: CH activation enabled discovery of a new ring system of 12H-Indazolo[2,1-a]cinnolin-12-ones with anti-proliferation activity

Meeting organometallic chemistry with drug discovery: CH activation enabled discovery of a new ring system of 12H-Indazolo[2,1-a]cinnolin-12-ones with anti-proliferation activity

  • Bioorg Med Chem Lett. 2020 Feb 15;30(4):126916. doi: 10.1016/j.bmcl.2019.126916.
Xiang Zhang 1,  Ruisong Bai 2,  Huan Xiong 3,  Hongtao Xu 4,  Wei Hou 5
Affiliations

Affiliations

  • 1 Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China. Electronic address: fcczhangx@zzu.edu.cn.
  • 2 College of Pharmaceutical Science, and Institute of Drug Development & Chemical Biology (IDD&CB), Zhejiang University of Technology, Hangzhou 310014, China.
  • 3 Shanghai Institute for Advanced Immunochemical Studies (SIAIS), ShanghaiTech University, Shanghai, China.
  • 4 Shanghai Institute for Advanced Immunochemical Studies (SIAIS), ShanghaiTech University, Shanghai, China. Electronic address: xuht@shanghaitech.edu.cn.
  • 5 College of Pharmaceutical Science, and Institute of Drug Development & Chemical Biology (IDD&CB), Zhejiang University of Technology, Hangzhou 310014, China. Electronic address: houwei@zjut.edu.cn.
PMID: 31889668 DOI: 10.1016/j.bmcl.2019.126916
Abstract

A diverse library of new ring system 12H-indazolo[2,1-a]cinnolin-12-ones have been synthesized efficiently via Ru (II) and Rh (III) catalyzed tandem CH alkylation/[4 + 2] annulation with diazo compounds in high to excellent yields. For the first time, we evaluated the biological activity of these compounds with this new skeleton and found some compounds exhibited high cytotoxic activity against human PC-3 and PANC-1 tumor cell lines with nanomolar IC50. Among them, the most potent compound 36 showed broad-spectrum cytotoxic activities against a series of human tumor cell lines derived from different organs (IC50 ~ 41 to 197 nM). Moreover, preliminary mechanistic studies indicated that 36 could inhibit the colony formation, cause cell cycle arrest and induce Apoptosis of PC-3 Cancer cells in a dose-dependent manner. Further intracellular mechanisms investigation found that 36 treatments could dose-dependently decrease the levels of Caspase-3 and PARP and up-regulate the level of cleaved PARP. These results suggested that 36 is a novel compound with good potential in the treatment of human cancers and worthy of further investigation.

Keywords

Anti-cancer; Apoptosis; CH activation; Molecular hybridization; New heterocyclic skeleton.

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