Novel tricyclic poly (ADP-ribose) polymerase-1/2 inhibitors with potent anticancer chemopotentiating activity: Design, synthesis and biological evaluation

Hui Li; Yan Hu; Xueyan Wang; Guangwei He; Yungen Xu; Qihua Zhu

doi:10.1016/j.bmc.2016.08.016

Novel tricyclic poly (ADP-ribose) polymerase-1/2 inhibitors with potent anticancer chemopotentiating activity: Design, synthesis and biological evaluation

Bioorg Med Chem. 2016 Oct 1;24(19):4731-4740. doi: 10.1016/j.bmc.2016.08.016. Epub 2016 Aug 11.

Authors

Hui Li¹, Yan Hu², Xueyan Wang¹, Guangwei He³, Yungen Xu⁴, Qihua Zhu⁴

Affiliations

¹ Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 21009, China.
² Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 21009, China.
³ Hefei YiGong Pharmaceutical Co. Ltd, Hefei 230088, China.
⁴ Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 21009, China; Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 21009, China.

PMID: 27561983
DOI: 10.1016/j.bmc.2016.08.016

Abstract

8,9-Dihydro-2,4,7,9a-tetraazabenzo[cd]azulen-6(7H)-ones were designed and synthesized as a new class of PARP-1/2 inhibitors. The compounds displayed a variable pattern of PARP-1/2 enzymes inhibition profile that, in part, paralleled the antiproliferative activity in cell lines. Among them, compound 9e exhibited not only the significant IC50 value of 28nM in the PARP-1 and 7.7nM in PARP-2 enzyme assay, but also a profound synergic efficacy combined with temozolomide with PF50 values of 2.6, 2.5, and 6.5 against MDA-MB-468, SW-620 and A549 and cell line, respectively.

Keywords: Anticancer; Inhibitors; PARP-1/2; Tricyclic.

Publication types

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

MeSH terms

Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology*
Azulenes / chemistry*
Azulenes / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Design
Humans
Models, Molecular
Neoplasms / drug therapy
Neoplasms / enzymology
Neoplasms / pathology
Poly (ADP-Ribose) Polymerase-1 / antagonists & inhibitors
Poly (ADP-Ribose) Polymerase-1 / metabolism
Poly(ADP-ribose) Polymerase Inhibitors / chemistry*
Poly(ADP-ribose) Polymerase Inhibitors / pharmacology*
Poly(ADP-ribose) Polymerases / metabolism

Substances

Antineoplastic Agents
Azulenes
Poly(ADP-ribose) Polymerase Inhibitors
PARP2 protein, human
Poly (ADP-Ribose) Polymerase-1
Poly(ADP-ribose) Polymerases