Design, synthesis and biological evaluation of novel molecules as potent PARP-1 inhibitors

Hui Shen; Yiran Ge; Junwei Wang; Hui Li; Yungen Xu; Qihua Zhu

doi:10.1016/j.bmcl.2021.128169

Design, synthesis and biological evaluation of novel molecules as potent PARP-1 inhibitors

Bioorg Med Chem Lett. 2021 Sep 1:47:128169. doi: 10.1016/j.bmcl.2021.128169. Epub 2021 Jun 6.

Authors

Hui Shen¹, Yiran Ge², Junwei Wang¹, Hui Li¹, Yungen Xu³, Qihua Zhu⁴

Affiliations

¹ Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 211198, China.
² Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China.
³ Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 211198, China; Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China. Electronic address: xyg64@126.com.
⁴ Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 211198, China; Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China. Electronic address: zhuqihua@vip.126.com.

PMID: 34091044
DOI: 10.1016/j.bmcl.2021.128169

Abstract

Two series of novel compounds with inhibition activity against PARP-1 were designed and synthesized. All target compounds were evaluated for their PARP-1 inhibition activity, and compounds with high PARP-1 inhibition activity were selected to assess for cellular assays in vitro. Among them, compound II-4 displayed impressive results in both PARP-1 enzyme inhibition with IC₅₀ value of 0.51 nM and anti-proliferation activity against HCT116 and HCC1937 cell lines with IC₅₀ values of 6.62 nM and 12.65 nM, respectively. Also, II-4 exhibited good metabolic stability in vitro with t_1/2 of 173.25 min and CL_int of 0.04 mL/min/mg. Prediction of molecular properties and protein docking were applied to structure design. Our study provides potential lead compounds and design directions for the development of PARP-1 inhibitors.

Keywords: Antitumor drug; DNA repair; Drug design; PARP-1 inhibitors.

Publication types

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

MeSH terms

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

Substances

Antineoplastic Agents
Poly(ADP-ribose) Polymerase Inhibitors
PARP1 protein, human
Poly (ADP-Ribose) Polymerase-1