Synthesis and biological evaluation of substituted 4-(thiophen-2-ylmethyl)-2H-phthalazin-1-ones as potent PARP-1 inhibitors

Ling-xiao Wang; Xin-bo Zhou; Meng-liang Xiao; Ning Jiang; Feng Liu; Wen-xia Zhou; Xiao-kui Wang; Zhi-bing Zheng; Song Li

doi:10.1016/j.bmcl.2014.07.001

Synthesis and biological evaluation of substituted 4-(thiophen-2-ylmethyl)-2H-phthalazin-1-ones as potent PARP-1 inhibitors

Bioorg Med Chem Lett. 2014 Aug 15;24(16):3739-43. doi: 10.1016/j.bmcl.2014.07.001. Epub 2014 Jul 5.

Authors

Ling-xiao Wang¹, Xin-bo Zhou¹, Meng-liang Xiao¹, Ning Jiang², Feng Liu², Wen-xia Zhou², Xiao-kui Wang³, Zhi-bing Zheng⁴, Song Li¹

Affiliations

¹ Laboratory of Computer-Aided Drug Design & Discovery, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, PR China.
² Department of Traditional Chinese Materia Medica and Neuroimmunopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, PR China.
³ Laboratory of Computer-Aided Drug Design & Discovery, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, PR China. Electronic address: wxkcaptain@aliyun.com.
⁴ Laboratory of Computer-Aided Drug Design & Discovery, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, PR China. Electronic address: zhengzb@bmi.ac.cn.

PMID: 25086680
DOI: 10.1016/j.bmcl.2014.07.001

Abstract

We have developed a series of substituted 4-(thiophen-2-ylmethyl)-2H-phthalazin-1-ones as potent PARP-1 inhibitors. Preliminary biological evaluation indicated that most compounds possessed inhibitory potencies comparable to, or higher than AZD-2281. Among these compounds, 18q appeared to be the most notable one, which displayed an 8-fold improvement in enzymatic activity compared to AZD-2281. These efforts lay the foundation for our further investigation.

Keywords: 4-(Thiophen-2-ylmethyl)-2H-phthalazin-1-ones; Antitumor; Biological evaluation; PARP-1 inhibitor; Synthesis.

Publication types

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

MeSH terms

Dose-Response Relationship, Drug
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
Molecular Structure
Phthalazines / chemical synthesis
Phthalazines / chemistry
Phthalazines / pharmacology*
Poly (ADP-Ribose) Polymerase-1
Poly(ADP-ribose) Polymerase Inhibitors*
Poly(ADP-ribose) Polymerases / metabolism
Structure-Activity Relationship
Thiophenes / chemical synthesis
Thiophenes / chemistry
Thiophenes / pharmacology*

Substances

Enzyme Inhibitors
Phthalazines
Poly(ADP-ribose) Polymerase Inhibitors
Thiophenes
PARP1 protein, human
Poly (ADP-Ribose) Polymerase-1
Poly(ADP-ribose) Polymerases