Chiral platinum(II) metallointercalators with potent in vitro cytotoxic activity

Four platinum(II) metallointercalating complexes of 1,10-phenanthroline (phen) with the chiral ancillary ligands trans-R,R- and trans-S,S-1,2-diaminocyclohexane (R,R- and S,S-dach, respectively), and N,N-dimethyl-R,R- and N,N-dimethyl-S,S-1,2-diaminocyclohexane (Me2-R,R-dach and Me2-S,S-dach, respectively) have been synthesised and characterised. The crystal structure of [Pt(Me2-S,S-dach)(phen)](ClO4)21.5 H2O (C20H26Cl2N4O9.5Pt) has been determined; orthorhombic, space group P212121(No. 19), a=23.194(8), b=25.131(9), c=8.522(3) Ã…. In vitro cytotoxic assays (IC50) in the human bladder cancer cell line 5637 and in the murine leukemia L1210 cell line revealed that [Pt(S,S-dach)(phen)](ClO4)2 (0.091 and 0.13 M, respectively) and [Pt(R,R-dach)(phen)](ClO4)2 (0.54 and 1.50 M, respectively) were more cytotoxic than cisplatin (0.31 and 0.50 M, respectively) and considerably more cytotoxic than their methylated counterparts, [Pt(Me2-R,R-dach)(phen)](ClO4)2 and [Pt(Me2-S,S-dach)(phen)](ClO4)2 (both>23 M). Chiral discrimination for [Pt(S,S-dach)(phen)](ClO4)2 over its R,R-enantiomer was observed in all 13 cancer cell lines investigated. Moreover, [Pt(S,S-dach)(phen)](ClO4)2 was more active than cisplatin in all cell lines tested and shows only partial cross-resistance to cisplatin in two cisplatin resistant cell lines.