Multi-targeted organometallic ruthenium(II)-arene anticancer complexes bearing inhibitors of poly(ADP-ribose) polymerase-1: A strategy to improve cytotoxicity.
Small-molecule inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1) have currently drawn much attention as promising chemotherapeutic drug candidates, and there is a need to develop more potent PARP inhibitors with improved bioavailability. Here we report a strategy to improve the cytotoxicity of PARP inhibitors by conjugation with organometallic ruthenium(II)-arene compounds. We also report a systematic study to reveal the mechanism of action of these ruthenium-PARP inhibitor conjugates. The complexes have been synthesized and characterized spectroscopically. The improved antiproliferative activity from the as-prepared complexes in four human cancer cell lines has indicated their potential for further development as antitumor drugs. Cellular uptake study reveals that the most active complex 3 easily entered into cells. Target validation assays show that the complexes inhibited PARP-1 slightly better than the original PARP inhibitors, that complex 3 strongly bound to DNA and inhibited transcription, and that this complex arrested the cell cycle at the G0/G1 stage. This type of information could shed light on the design of the next generation of more active ruthenium-PARP inhibitor conjugates.
Department of Biology and Chemistry, City University of Hong Kong, Kowloon Tong, Hong Kong, China.
Zhigang
Z
Wang
Department of Chemistry, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
Hui
H
Qian
Department of Biology and Chemistry, City University of Hong Kong, Kowloon Tong, Hong Kong, China.
Shek-Man
SM
Yiu
Department of Chemistry, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
Jianwei
J
Sun
Department of Biology and Chemistry, City University of Hong Kong, Kowloon Tong, Hong Kong, China. Electronic address: guangzhu@cityu.edu.hk.
Guangyu
G
Zhu
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D018360:Crystallography, X-Ray; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006868:Hydrolysis; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry* / Q000494:pharmacology*; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D012428:Ruthenium / Q000737:chemistry*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009942:Organometallic Compounds; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D012428:Ruthenium; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases
Multi-targeted anticancer agent; PARP-1 inhibitor; Ruthenium(II)–arene complex; Transcription inhibition