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

Abstract

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 (Me(2)-R,R-dach and Me(2)-S,S-dach, respectively) have been synthesised and characterised. The crystal structure of [Pt(Me(2)-S,S-dach)(phen)](ClO(4))(2)1.5 H(2)O (C(20)H(26)Cl(2)N(4)O(9.5)Pt) has been determined; orthorhombic, space group P2(1)2(1)2(1)(No. 19), a=23.194(8), b=25.131(9), c=8.522(3) A. In vitro cytotoxic assays (IC(50)) in the human bladder cancer cell line 5637 and in the murine leukemia L1210 cell line revealed that [Pt(S,S-dach)(phen)](ClO(4))(2) (0.091 and 0.13 microM, respectively) and [Pt(R,R-dach)(phen)](ClO(4))(2) (0.54 and 1.50 microM, respectively) were more cytotoxic than cisplatin (0.31 and 0.50 microM, respectively) and considerably more cytotoxic than their methylated counterparts, [Pt(Me(2)-R,R-dach)(phen)](ClO(4))(2) and [Pt(Me(2)-S,S-dach)(phen)](ClO(4))(2) (both>23 microM). Chiral discrimination for [Pt(S,S-dach)(phen)](ClO(4))(2) over its R,R-enantiomer was observed in all 13 cancer cell lines investigated. Moreover, [Pt(S,S-dach)(phen)](ClO(4))(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.

• Authors: Dianne M Fisher, Patrick J Bednarski, Renate Grünert, Peter Turner, Ronald R Fenton, Janice R Aldrich-Wright
• Journal: ChemMedChem (ChemMedChem) Vol. 2 Issue 4 Pg. 488-95 (Apr 2007) ISSN: 1860-7187 [Electronic] Germany
• PMID: 17340669 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Intercalating Agents
• Platinum Compounds

Topics

• Antineoplastic Agents (chemical synthesis, pharmacology)
• Cell Line, Tumor
• Humans
• Intercalating Agents (chemical synthesis, pharmacology)
• Models, Molecular
• Molecular Structure
• Platinum Compounds (chemical synthesis, pharmacology)
• Structure-Activity Relationship