2. Academic Validation
  3. Discovery of Novel Bromophenol-Thiosemicarbazone Hybrids as Potent Selective Inhibitors of Poly(ADP-ribose) Polymerase-1 (PARP-1) for Use in Cancer

Discovery of Novel Bromophenol-Thiosemicarbazone Hybrids as Potent Selective Inhibitors of Poly(ADP-ribose) Polymerase-1 (PARP-1) for Use in Cancer

  • J Med Chem. 2019 Mar 28;62(6):3051-3067. doi: 10.1021/acs.jmedchem.8b01946.
Chuanlong Guo 1 2 3 4 5,  Lijun Wang 1 2 3,  Xiuxue Li 1 2 3,  Shuaiyu Wang 1 2 3,  Xuemin Yu 6,  Kuo Xu 1 2 3,  Yue Zhao 1 2 3,  Jiao Luo 1 2 3 5,  Xiangqian Li 1 2 3,  Bo Jiang 1 2 3,  Dayong Shi 1 2 7 3
Affiliations

Affiliations

  • 1 Key Laboratory of Experimental Marine Biology , Institute of Oceanology, Chinese Academy of Sciences , Qingdao 266071 , Shandong , China.
  • 2 Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology , Qingdao 266071 , Shandong , China.
  • 3 Center for Ocean Mega-Science , Chinese Academy of Sciences , Qingdao 266071 , Shandong , China.
  • 4 Department of Pharmacy, College of Chemical Engineering , Qingdao University of Science and Technology , Qingdao 266042 , China.
  • 5 University of Chinese Academy of Sciences , Beijing 100049 , China.
  • 6 Department of Otorhinolaryngology , Qilu Hospital of Shandong University , Qingdao 266000 , Shandong , China.
  • 7 State Key Laboratory of Microbial Technology , Shandong University , Jinan 250100 , Shandong , China.
PMID: 30844273 DOI: 10.1021/acs.jmedchem.8b01946
Abstract

Poly(ADP-ribose) polymerase-1 (PARP-1) is a new potential target for Anticancer drug discovery. A series of bromophenol-thiosemicarbazone hybrids as PARP-1 inhibitors were designed, synthesized, and evaluated for their antitumor activities. Among them, the most promising compound, 11, showed excellent selective PARP-1 inhibitory activity (IC50 = 29.5 nM) over PARP-2 (IC50 > 1000 nM) and potent Anticancer activities toward the SK-OV-3, Bel-7402 and HepG2 Cancer cell lines (IC50 = 2.39, 5.45, and 4.60 μM), along with inhibition of tumor growth in an in vivo SK-OV-3 cell xenograft model. Further study demonstrated that compound 11 played an antitumor role through multiple Anticancer mechanisms, including the induction of Apoptosis and cell cycle arrest, cellular accumulation of DNA double-strand breaks, DNA repair alterations, inhibition of H2O2-triggered PARylation, antiproliferative effects via the production of cytotoxic Reactive Oxygen Species, and Autophagy. In addition, compound 11 displayed good pharmacokinetic characteristics and favorable safety. These observations demonstrate that compound 11 may serve as a lead compound for the discovery of new Anticancer drugs.

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