Effect of chirality on the anticancer activity of Pt( II ) and Pt( IV ) complexes containing 1 R ,2 R and 1 S ,2 S enantiomers of the trans -1,2-diamino-4-cyclohexene ligand (DACHEX), an analogue of diaminocyclohexane used in oxaliplatin
Six enantiomerically pure, oxaliplatin-like, platinum compounds (two platinum(ii) and four platinum(iv)), all containing unsaturated cyclic diaminetrans-1,2-diamino-4-cyclohexene (DACHEX) as a substitute for thetrans-1,2-diaminocyclohexane used in oxaliplatin, were investigated. The complexes were characterized by elemental analyses, ESI-MS, and1H-NMR spectroscopy. For the four Pt(iv) complexes the electrochemical redox behaviour, investigated by cyclic voltammetry, showed that all complexes possess reduction potentials suitable for activationin vivo. The antiproliferative activity was assessedin vitroon human cancer cell lines, also selected for resistance to platinum-based drugs or belonging to the MultiDrug-Resistant (MDR) phenotype. All complexes exhibited antiproliferative activity superior to that of cisplatin and almost equivalent to or better than that of oxaliplatin; moreover, most complexes were also capable of overcoming both the cisplatin- and the oxaliplatin-resistance. By comparing the effectiveness of the enantiomerically pure compounds with the racemic one, theR,Renantiomer emerged as the most effective in the case of Pt(ii) complexes whereas theS,Senantiomer was the most effective in the case of the Pt(iv) derivatives. From the results obtained also against 3D spheroid tumor models,cis,trans,cis-[Pt(OXA)(OBz)2(1S,2S-DACHEX)] (OBz = benzoate) emerged as the most promising candidate for further preclinical investigation.
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Papadia, P., Barbanente, A., Ditaranto, N., Hoeschele, J. D., Natile, G., Marzano, C., Gandin, V., & Margiotta, N. (2021). Effect of chirality on the anticancer activity of Pt( II ) and Pt( IV ) complexes containing 1 R ,2 R and 1 S ,2 S enantiomers of the trans -1,2-diamino-4-cyclohexene ligand (DACHEX), an analogue of diaminocyclohexane used in oxaliplatin. Dalton Transactions, 50(43), 15655–15668. https://doi.org/10.1039/D1DT02255E