Design, synthesis and antiproliferative activity of a novel class of indole-2-carboxylate derivatives

Xing-yue Ji; Si-tu Xue; Yue-chen Zhan; Jia-jia Shen; Lin-tao Wu; Jie Jin; Zhen Wang; Zhuo-rong Li

doi:10.1016/j.ejmech.2014.05.043

Design, synthesis and antiproliferative activity of a novel class of indole-2-carboxylate derivatives

Eur J Med Chem. 2014 Aug 18:83:409-18. doi: 10.1016/j.ejmech.2014.05.043. Epub 2014 May 15.

Authors

Xing-yue Ji¹, Si-tu Xue¹, Yue-chen Zhan¹, Jia-jia Shen¹, Lin-tao Wu¹, Jie Jin¹, Zhen Wang², Zhuo-rong Li³

Affiliations

¹ Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China.
² Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China. Electronic address: wangzhen@imb.pumc.edu.cn.
³ Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China. Electronic address: lizhuorong@imb.pumc.edu.cn.

PMID: 24996136
DOI: 10.1016/j.ejmech.2014.05.043

Abstract

Based on the chemical structure of Pyrroloquinoline quinone (PQQ), a novel class of indole-2-carboxylate derivatives was designed, synthesized and assayed for antiproliferative activity in cancer cells in vitro. The biological results showed that some derivatives exhibited significant antiproliferative activity against HepG2, A549 and MCF7 cells. Notably, the novel compounds, methyl 6-amino-4-cyclohexylmethoxy-1H-indole-2-carboxylate (6e) and methyl 4-isopropoxy-6-methoxy-1H-indole-2-carboxylate (9l) exhibited more potent antiproliferative activity than the reference drugs PQQ and etoposide in vitro, with IC50 values ranging from 3.78 ± 0.58 to 24.08 ± 1.76 μM. Further biological assay showed that both compounds 6e and 9l increased ROS generation dose-dependently, and induced PARP cleavage in A549 cells. Consequently, 6e and 9l appeared as promising anticancer lead compounds for further optimization.

Keywords: Antiproliferative activities; Indole-2-carboxylate derivatives; PQQ; ROS generation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Cycle / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Chemistry Techniques, Synthetic
Drug Design*
Drug Screening Assays, Antitumor
Humans
Indoles / chemical synthesis*
Indoles / chemistry
Indoles / pharmacology*
Inhibitory Concentration 50
Intracellular Space / drug effects
Intracellular Space / metabolism
Poly(ADP-ribose) Polymerases / metabolism
Proteolysis / drug effects
Reactive Oxygen Species / metabolism
Structure-Activity Relationship

Substances

Antineoplastic Agents
Indoles
Reactive Oxygen Species
indole-2-carboxylate
Poly(ADP-ribose) Polymerases