title: Platinated benzonaphthyridone is a stronger inhibitor of poly(ADP-ribose) polymerase-1 and a more potent anticancer agent than is the parent inhibitor.
abstract: Inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1) have shown to be promising in clinical trials against cancer and other diseases, and lots of efforts have been put into the development of organic compounds as more potent PARP-1 inhibitors. Here we describe a strategy to conveniently obtain metal-based PARP-1 inhibitors with enhanced biological activities by conjugating platinum moiety with an original inhibitor, e.g., benzonaphthyridone. Based on the structure-activity relationship analysis of PARP-1 inhibitors, three platinated PARP-1 inhibitors were designed, and the complexes were synthesized and characterized. Complex 3 presented significantly enhanced cytotoxicity against a panel of human cancer cells and a 10-fold increased inhibitory effect against recombinant PARP-1 compared with the original PARP-1 inhibitor. Complex 3 was as cytotoxic as cisplatin and its spectrum of anticancer activity was identical to that of cisplatin. The complex was able to enter into cancer cells efficiently, bind to DNA well, and block cell cycle at G₂/M phase, indicating that complex 3 is an effective anticancer agent with a distinct mechanism of action. Our study implies that the conjugation of platinum with PARP-1 inhibitors could be a valid strategy to obtain more potent anticancer agents with improved biological activities.
authors.affiliation: Department of Biology and Chemistry, City University of Hong Kong, Kowloon Tong, Hong Kong, China; Biotech and Health Centre, Shenzhen Research Institute of City University of Hong Kong, Shenzhen, China.
authors.forename: Beilei
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Chemistry, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Qian
authors.affiliation: Department of Biology and Chemistry, City University of Hong Kong, Kowloon Tong, Hong Kong, China.
authors.forename: Shek-Man
authors.initials: SM
authors.lastname: Yiu
authors.affiliation: Department of Chemistry, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
authors.forename: Jianwei
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Biology and Chemistry, City University of Hong Kong, Kowloon Tong, Hong Kong, China; Biotech and Health Centre, Shenzhen Research Institute of City University of Hong Kong, Shenzhen, China. Electronic address: guangzhu@cityu.edu.hk.
authors.forename: Guangyu
authors.initials: G
authors.lastname: Zhu
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D009287:Naphthyridines / Q000737:chemistry* / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000494:pharmacology*; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009287:Naphthyridines; D009944:Organoplatinum Compounds; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C006029:benzonaphthyridone; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D002945:Cisplatin
keywords: Anticancer agents; Cisplatin; DNA damage repair; Poly(ADP-ribose) polymerase-1 inhibitors