The Relation Between Stereochemistry and Biological Activity of Platinum(II) Complexes Chelated with Chiral Diamine Ligands: An Intricate Problem

Abstract

Abstract:The origin of activity differences between stereoisomers of anticancer platinum(II) complexes chelated with chiral diamine ligands has been almost exclusively explained by diastereoselective interactions with DNA. Although this model has been widely accepted in vitro and in vivo experiments showed some conflicting results, leading to the conclusion that other biomolecules might be responsible for this stereoselectivity as well. These compounds, called bionucleophiles, are in most instances amino acids or proteins present in biological fluids. As these chiral molecules are very reactive towards the platinum complexes, they may contribute to stereoselectivity, but also to resistance and toxicity. This review gives a general survey of chiral platinum(II) complexes and their interactions with DNA. The bionucleophiles which have been identified and the consequences of their reaction with platinum(II) complexes are discussed. Analytical techniques used to investigate interactions between established and potential chiral platinum drugs and bionucleophiles are presented.

Neutral and ionic platinum compounds containing a cyclometallated chiral primary amine: synthesis, antitumor activity, DNA interaction and topoisomerase I–cathepsin B inhibition

“…1 Since double-helical DNA has a chiral structure, the stereochemistry of the adducts formed with complexes containing enantiomeric ligands can influence the antitumor activity. [3][4][5] Moreover, it is interesting to point out that three out of the six platinum compounds (namely oxaliplatin, lobaplatin and heptaplatin) approved for clinical use have a chiral structure (see Chart 1). The negligible difference generally observed for the biological activities of the enantiomers was related to the free rotation that offset any stereospecificity in the interactions with biological substrates.…”

“…2 Early studies carried out for compounds cis-[PtX 2 A 2 ] (A = amine ligand and X = anionic ligand), indicated that the activity decreases in the order A = NH 3 > RNH 2 > R 2 NH, and, therefore, most investigations concerning chiral monodentate ligands were restricted to platinum complexes with primary amines. 1,5 On the other hand, cycloplatinated complexes have raised great interest as anticancer agents, 6,7 and compounds containing either bidentate [C,N] [8][9][10][11][12][13][14][15][16][17][18][19][20][21] or terdentate [C,N,N′] [22][23][24][25][26][27] ligands have been tested against tumor cells with very promising results. The degree of rotational freedom can be reduced using chelate ligands, an outstanding example being oxaliplatin, a third generation anti-cancer drug containing trans-1R,2R-diaminocyclohexane.…”

Editorial [Hot Topic: Target Specificity of Effective Anticancer Therapeutics (Executive Editor: G. Capranico)]

“…Dufrasne and Galanski [4] present the case of platinum complexes. The authors discuss the mode of interaction with DNA of anticancer platinum(II) complexes and their relevant pharmacological effects.…”

Synthesis and in vitro antitumor activity of novel iridium(III) complexes with enantiopure C2-symmetrical vicinal diamine ligands

“…Furthermore, bulk of investigative results have demonstrated that the stereochemistry of the diamine ligands of platinum compounds with chiral C-substituted ethylenediamines had an important influence on their interactions of DNA, anticancer activity, toxicity, and resistance. 25,26 Particularly, it has been reported that optically pure (1,2-diarylethane-1,2-diamine)dichloroplatinum(II) complexes induce significant inhibitory effects on the growth of leukemic and tumor cells, and a distinctly better effect was generally observed with the R,R/S,S configurations compared with the R,S counterparts. [27][28][29][30] These results motivated us to apply the findings from platinum(II) complexes to iridium(III) complexes.…”