Sterically hindered complexes of platinum(II) with planar heterocyclic nitrogen donors. A novel complex with 1-methyl-cytosine has a spectrum of activity different from cisplatin and is able of overcoming acquired cisplatin resistance

A very interesting series of water sol. platinum compds. violating some of the classical structure-activity relations, but still showing antitumor activity, was reported by Hollis and collaborators some 25 years ago. The compds., [PtClA2L]+ (A2 = two monodentate or a bidentate amine, L = a secondary or tertiary amine or a N-donor heterocycle), were characterized by a pos. charge and three non-labile N-donor ligands. The authors have extended the study to analogous compds., [PtI(Me2phen)L]I, in which 2,9-dimethyl-1,10-phenanthroline has taken the place of the A2 ligand(s) and L is 2-picoline (1), 6-amino-2-picoline (2), or 1-methylcytosine (3). The x-ray anal. of 2 revealed a bow-like distortion of the phenanthroline plane, a sloping of the phenanthroline plane with respect to the coordination plane, and an overall shielding of the metallic core by the ortho substituents of the phenanthroline and pyridine ligands. In vitro grow inhibition assays were performed on the most water sol. complex 3. This complex was characterized by a potent growth inhibitory activity with mean IC50 value (in a panel of 11 human tumor cell lines) of 1.1 .mu.M to be compared with a mean value of 3.8 .mu.M for cisplatin. The same compd. also appears to completely overcome the acquired cisplatin resistance stemming from reduced uptake or a multifocal mechanism, thus pointing to a mechanism of action distinctly different from that of cisplatin.