Multi-targeted organometallic ruthenium(II)–arene anticancer complexes bearing inhibitors of poly(ADP-ribose) polymerase-1: A strategy to improve cytotoxicity

• Ruthenium(II)-arene complexes bearing PARP-1 inhibitors have been synthesized.
• The complexes showed improved cytotoxicities compared with PARP-1 inhibitors.
• Complex 3 inhibited PARP-1, bound to DNA, and inhibited transcription.

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.

Ruthenium–PARP inhibitor conjugates: Organometallic ruthenium(II)–arene complexes bearing PARP inhibitors showed increased cytotoxicity as promising anticancer agents. The complexes enter into cancer cells well and have multi-targeted properties: on one hand, they bind to DNA and inhibit transcription; on the other hand, they inhibit the catalytic activity of PARP.Figure optionsDownload as PowerPoint slide