| Cancer is emerging as a major problem globally, both in more developed and in less developed countries. Anticancer platinum(II) compounds, e.g. cisplatin, carboplatin, and oxaliplatin, are administered in more than50%of the treatment regimes used for patients suffering from cancer. However, the clinical success of these drugs is compromised by severe side effects (e.g., nephrotoxicity, ototoxicity, and neurotoxicity) and spontaneous or acquired resistance. Therefore, it is of much urgency to develop new metal-based anticancer drugs with reduced toxicity, increased anticancer activity and less tumor resistance.Based on the findings discovered in researches of mechanism and SAR studies of classical platinum(II) species, we focused on iridium(Ⅲ) complexes, which have been widely ignored in the search for novel metal-based anticancer drugs. Chiral vicinal diamines were, for the first time, introduced to the metal as a bidentate ligand to prepare novel iridium(II) complexes. Twenty two iridium(Ⅲ) complexes with enantiopure C2symmetrical vicinal diamines and thirteen with enantiopure C2asymmetrical vicinal diamines were synthesized, characterized by FT-IR,1H NMR,13C NMR and FT-MS along with a single crystal X-ray diffraction for a representative compound. Meanwhile, thirteen iridium(III) complexes with2-phenylpiridine analogues as a bidentate ligand and acetonitrile as a monodentate ligand were synthesized and characterized as well for a wide diversity of structure. Antitumor evaluation in vitro and SAR studies of the three newly synthesized type of iridium(III) complexes were performed. In addition, twelve platinum(II) complexes with chiral vicinal diamines were synthesized to complete the work devoted to synthesis and antitumor evaluation of Platinum(II) complexes with enantiopure C2-asymmetrical vicinal diamines in our group’s previous researches.The cytotoxicities of all of the complexes against the human solid tumor cell lines A2780, A549, KB, and MDA-MB-231were evaluated. Of the three structurally different type of iridium(III) complexes, the series of iridium(III) complexes with enantiopure C2symmetrical vicinal diamines showed the most promising anticancer activity. Six compounds of this type exhibited more potent or similar activity compared with oxaliplatin, and a pronounced enantioselectivity of the activity between (R,R)-and (S,S)-isomers was observed on all the tested tumor cell lines. The (R,R)-configured complexes exhibited potent or moderate activity, whereas their corresponding (S,S)-isomers were found to be mostly inactive. Furthermore, the representative compound trans-68d with attractive cytotoxicity was chose for preliminary mechanism studies. The flow cytometric and western blotting analysis revealed that the mode of cell death initiated by trans-68d was p53-mediated apoptosis. In addition, the preliminary evaluation of the acute toxicity demonstrated that this compound was less toxic than oxaliplatin.Besides, nine iridium(III) complexes from the three type were selected for intracellular fluorescent imaging studies with a laser confocal fluorescent microscope. The results showed that seven compounds out of the nine emitted fluorescence in KB cells, and all of them distributed in the cytoplasm, which laid a foundation for us to identify the target in the future.To sum up, emphasizing on the synthesis and antitumor activity of novel iridium(III) complexes with enantiopure vicinal diamines, plenty of innovative and hard work has been done. These studies had been financial supported by National Natural Science Foundation of China (No.81172920), Shanghai Municipal Committee of Science and Technology (No.10431903100). |
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