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.
Huan Long  1 ,  Xiaolong Hu  1 ,  Baolin Wang  1 ,  Quan Wang  1 ,  Rong Wang  1 ,  Shumeng Liu  1 ,  Fei Xiong  2 ,  Zhenzhou Jiang  3 ,  Xiao-Qi Zhang  4 ,  Wen-Cai Ye  4 ,  Hao Wang  1
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.

Products