2. Academic Validation
  3. Design, combinatorial synthesis and biological evaluations of novel 3-amino-1'-((1-aryl-1H-1,2,3-triazol-5-yl)methyl)-2'-oxospiro[benzo[a] pyrano[2,3-c]phenazine-1,3'-indoline]-2-carbonitrile antitumor hybrid molecules

Design, combinatorial synthesis and biological evaluations of novel 3-amino-1'-((1-aryl-1H-1,2,3-triazol-5-yl)methyl)-2'-oxospiro[benzo[a] pyrano[2,3-c]phenazine-1,3'-indoline]-2-carbonitrile antitumor hybrid molecules

  • Eur J Med Chem. 2017 Jul 28:135:125-141. doi: 10.1016/j.ejmech.2017.04.040.
Yuanyuan Lu 1,  Linlin Wang 2,  Xiaobing Wang 3,  Tao Xi 2,  Jianmin Liao 2,  Zhixiang Wang 4,  Feng Jiang 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China. Electronic address: luyy@cpu.edu.cn.
  • 2 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China.
  • 3 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
  • 4 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; School of Engineering, China Pharmaceutical University, Nanjing 210009, China.
  • 5 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; School of Engineering, China Pharmaceutical University, Nanjing 210009, China. Electronic address: daniel_chem@126.com.
PMID: 28441581 DOI: 10.1016/j.ejmech.2017.04.040
Abstract

A combinatorial chemical library of fifty-nine novel 3-amino-1'-((1-aryl-1H-1,2,3-triazol-5-yl)methyl)-2'-oxospiro[benzo[a]pyrano[2,3-c]phenazine-1,3'-indoline]-2-carbonitrile, designed as hybrid molecules of phenazine, pyran, indole and 1,2,3-triazole pharmacophores, were constructed in this study. Cytotoxic evaluation indicated that some compounds exhibited moderate cytotoxicity against HCT116, MCF7, HepG2 and A549 Cancer cell lines in vitro, in which compound 36 was found to have best antiproliferative activity against the A549 Cancer cell line with IC50 value of 5.4 μM. All compounds had low or no effect against L02 and HUVEC non-cancer cell lines. Compound 36 was further confirmed to mainly locate mitochondria in A549 Cancer cells via laser-scanning confocal microscopy. Moreover, compound 36 was proved to increase ROS production and induce cell cycle arrest in S phase. Western blot analysis illustrated Bax/Bcl-2 ratio was increased at dose-dependent manner, and both cleaved Caspase-3 and cleaved caspase-9 was enhanced by treated with compound 36. All the above evidences in vitro indicated that compound 36 might induce the Apoptosis of A549 Cancer cells via a mitochondria-dependent pathway.

Keywords

Antiproliferative activity; Apoptosis; Cell cycle; Hybrid molecules; Mitochondria; ROS.

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