Synthesis, biological evaluation and SAR studies of novel bicyclic antitumor platinum(IV) complexes

• Novel 1,2-bis(aminomethyl)bicyclic platinum(IV) complexes have been synthesized.
• Hydroxido (axial) and chlorido or malonato (equatorial) were used as labile ligands.
• The most active complexes were those having malonate as labile ligands.
• Lipophilic and symmetrical bicyclo[2.2.2]octane complexes were much more active.

The present study describes the synthesis, anticancer activity and SAR studies of novel platinum(IV) complexes having 1,2-bis(aminomethyl)carbobicyclic or oxabicyclic carrier ligands, bearing chlorido and/or hydroxido ligands in axial position and chlorido or malonato ligands in equatorial position (labile ligands). These complexes were synthetized with the aim of obtaining new anticancer principles more soluble in water and therefore more bioavailable. Several substitution patterns on the platinum atom have been designed in order to evaluate their antiproliferative activity and to establish structure–activity relationship rules. The synthesis of platinum(IV) complexes with axial hydroxyl ligands on the platinum(IV) were carried out by reaction of K2Pt(OH)2Cl4 with the corresponding diamines. The complexes with axial chlorido ligands on the platinum(IV) atom were synthesized by direct reaction of diamines with K2PtCl6. Carboxylated complexes were synthesized by the substitution reaction of equatorial chlorido ligands by silver dicarboxylates. The most actives complexes were those having malonate as a labile ligand, no matter of the structure of the carrier ligand. Regarding the influence of the structure of the non-labile 1,4-diamine carrier ligand on the cytotoxicity, it was found that the complexes having the more lipophilic and symmetrical bicyclo[2.2.2]octane framework were much more active than those having an oxygen or methylene bridge.

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