Identification of novel PARP-1 inhibitors: Drug design, synthesis and biological evaluation

Zhouling Xie; Youli Zhou; Wei Zhao; He Jiao; Yu Chen; Yong Yang; Zhiyu Li

doi:10.1016/j.bmcl.2015.08.060

Identification of novel PARP-1 inhibitors: Drug design, synthesis and biological evaluation

Bioorg Med Chem Lett. 2015 Oct 15;25(20):4557-61. doi: 10.1016/j.bmcl.2015.08.060. Epub 2015 Aug 22.

Authors

Zhouling Xie¹, Youli Zhou¹, Wei Zhao², He Jiao¹, Yu Chen¹, Yong Yang², Zhiyu Li³

Affiliations

¹ Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 21009, China.
² State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing 21009, China.
³ Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 21009, China. Electronic address: zhiyuli@cpu.edu.cn.

PMID: 26342868
DOI: 10.1016/j.bmcl.2015.08.060

Abstract

A series of AG014699 derivatives containing a novel scaffold of 2,3-dihydro-1H-[1,2]diazepino[4,5,6-cd]indole-1,4(6H)-dione were synthesized and evaluated for their inhibitory activities toward PARP-1 enzyme and two cell lines, MCF-7 cells and the BRCA1-deficient MDA-MB-436 cells. Our results demonstrated that of all AG014699 derivatives synthesized in this work, compounds 6 and 7 showed strong PARP-1 inhibitory activity (IC50=3.5 nM and 2.4 nM, respectively), only four and three times less potent than AG014699. Compound 6 also had significantly cell inhibitory activity against both MCF-7 cells (CC50=25.8 μM) and the BRCA1-deficient MDA-MB-436 cells (CC50=5.4 μM), nearly as good as AG014699, indicating that it can be a promising compound for further evaluation.

Keywords: BRCA1/2-deficient; DNA damage; Inhibitor; Molecular docking; Poly ADP-ribose polymerase-1 (PARP-1).

Publication types

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

MeSH terms

Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Humans
Indoles / chemical synthesis
Indoles / chemistry
Indoles / pharmacology*
Molecular Structure
Poly (ADP-Ribose) Polymerase-1
Poly(ADP-ribose) Polymerase Inhibitors / chemical synthesis
Poly(ADP-ribose) Polymerase Inhibitors / chemistry
Poly(ADP-ribose) Polymerase Inhibitors / pharmacology*
Poly(ADP-ribose) Polymerases / metabolism*
Structure-Activity Relationship

Substances

Indoles
Poly(ADP-ribose) Polymerase Inhibitors
rucaparib
PARP1 protein, human
Poly (ADP-Ribose) Polymerase-1
Poly(ADP-ribose) Polymerases