Discovery of Novel Apigenin-Piperazine Hybrids as Potent and Selective Poly (ADP-Ribose) Polymerase-1 (PARP-1) Inhibitors for the Treatment of Cancer

Huan Long; Xiaolong Hu; Baolin Wang; Quan Wang; Rong Wang; Shumeng Liu; Fei Xiong; Zhenzhou Jiang; Xiao-Qi Zhang; Wen-Cai Ye; Hao Wang

doi:10.1021/acs.jmedchem.1c00735

Discovery of Novel Apigenin-Piperazine Hybrids as Potent and Selective Poly (ADP-Ribose) Polymerase-1 (PARP-1) Inhibitors for the Treatment of Cancer

J Med Chem. 2021 Aug 26;64(16):12089-12108. doi: 10.1021/acs.jmedchem.1c00735. Epub 2021 Aug 18.

Authors

Huan Long¹, Xiaolong Hu¹, Baolin Wang¹, Quan Wang¹, Rong Wang¹, Shumeng Liu¹, Fei Xiong², Zhenzhou Jiang³, Xiao-Qi Zhang⁴, Wen-Cai Ye⁴, Hao Wang¹

Affiliations

¹ State Key Laboratory of Natural Medicines, Department of TCMs Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China.
² State Key Laboratory of Bioelectronics, Jiangsu Laboratory for Biomaterials and Devices, Southeast University, Nanjing 210009, People's Republic of China.
³ Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, People's Republic of China.
⁴ Institute of Traditional Chinese Medicine and Natural Products, Jinan University, Guangzhou 510632, People's Republic of China.

PMID: 34404206
DOI: 10.1021/acs.jmedchem.1c00735

Abstract

Poly (ADP-ribose) polymerase-1 (PARP-1) is a potential target for the discovery of chemosensitizers and anticancer drugs. Amentoflavone (AMF) is reported to be a selective PARP-1 inhibitor. Here, structural modifications and trimming of AMF have led to a series of AMF derivatives (9a-h) and apigenin-piperazine/piperidine hybrids (14a-p, 15a-p, 17a-h, and 19a-f), respectively. Among these compounds, 15l exhibited a potent PARP-1 inhibitory effect (IC₅₀ = 14.7 nM) and possessed high selectivity to PARP-1 over PARP-2 (61.2-fold). Molecular dynamics simulation and the cellular thermal shift assay revealed that 15l directly bound to the PARP-1 structure. In in vitro and in vivo studies, 15l showed a potent chemotherapy sensitizing effect against A549 cells and a selective cytotoxic effect toward SK-OV-3 cells through PARP-1 inhibition. 15l·2HCl also displayed good ADME characteristics, pharmacokinetic parameters, and a desirable safety margin. These findings demonstrated that 15l·2HCl may serve as a lead compound for chemosensitizers and the (BRCA-1)-deficient cancer therapy.

Publication types

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

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / metabolism
Antineoplastic Agents / pharmacokinetics
Antineoplastic Agents / therapeutic use*
Cell Line, Tumor
Drug Discovery
Female
Flavones / chemical synthesis
Flavones / metabolism
Flavones / pharmacokinetics
Flavones / therapeutic use*
Humans
Male
Mice
Mice, Inbred BALB C
Mice, Nude
Molecular Docking Simulation
Molecular Dynamics Simulation
Molecular Structure
Neoplasms / drug therapy*
Piperazines / chemical synthesis
Piperazines / metabolism
Piperazines / pharmacokinetics
Piperazines / therapeutic use*
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 / metabolism
Poly(ADP-ribose) Polymerase Inhibitors / pharmacokinetics
Poly(ADP-ribose) Polymerase Inhibitors / therapeutic use*
Protein Binding
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship

Substances

Antineoplastic Agents
Flavones
Piperazines
Poly(ADP-ribose) Polymerase Inhibitors
Poly (ADP-Ribose) Polymerase-1