Issue 43, 2021

Effect of chirality on the anticancer activity of Pt(ii) and Pt(iv) complexes containing 1R,2R and 1S,2S enantiomers of the trans-1,2-diamino-4-cyclohexene ligand (DACHEX), an analogue of diaminocyclohexane used in oxaliplatin

Abstract

Six enantiomerically pure, oxaliplatin-like, platinum compounds (two platinum(II) and four platinum(IV)), all containing unsaturated cyclic diamine trans-1,2-diamino-4-cyclohexene (DACHEX) as a substitute for the trans-1,2-diaminocyclohexane used in oxaliplatin, were investigated. The complexes were characterized by elemental analyses, ESI-MS, and 1H-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 activation in vivo. The antiproliferative activity was assessed in vitro on 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, the R,R enantiomer emerged as the most effective in the case of Pt(II) complexes whereas the S,S enantiomer 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.

Graphical abstract: Effect of chirality on the anticancer activity of Pt(ii) and Pt(iv) complexes containing 1R,2R and 1S,2S enantiomers of the trans-1,2-diamino-4-cyclohexene ligand (DACHEX), an analogue of diaminocyclohexane used in oxaliplatin

Supplementary files

Article information

Article type
Paper
Submitted
07 Jul 2021
Accepted
04 Oct 2021
First published
04 Oct 2021

Dalton Trans., 2021,50, 15655-15668

Effect of chirality on the anticancer activity of Pt(II) and Pt(IV) complexes containing 1R,2R and 1S,2S enantiomers of the trans-1,2-diamino-4-cyclohexene ligand (DACHEX), an analogue of diaminocyclohexane used in oxaliplatin

P. Papadia, A. Barbanente, N. Ditaranto, J. D. Hoeschele, G. Natile, C. Marzano, V. Gandin and N. Margiotta, Dalton Trans., 2021, 50, 15655 DOI: 10.1039/D1DT02255E

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