title: 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.
abstract: A very interesting series of water soluble platinum compounds violating some of the classical structure-activity relationships, but still showing antitumor activity, was reported by Hollis and collaborators some 25 years ago [L.S. Hollis, A.R. Amundsenm, E.W. Stern. J. Med. Chem. 32 (1989) 128-136]. The compounds, having formula [PtClA(2)L](+) (A(2)=two monodentate or a bidentate amine, L=a secondary or tertiary amine or a N-donor heterocycle), were characterized by a positive charge and three non-labile N-donor ligands. We have extended the investigation to analogous compounds in which 2,9-dimethyl-1,10-phenanthroline has taken the place of the A(2) ligand(s) and L is 2-picoline (1), 6-amino-2-picoline (2), or 1-methyl-cytosine (3). The X-ray analysis of 2 has 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 have been performed on the most water soluble complex 3. The results indicate that this complex is characterized by a potent growth inhibitory activity with mean IC(50) value (in a panel of 11 human tumor cell lines) of 1.1 microM to be compared with a mean value of 3.8 microM for cisplatin. The same compound 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.
authors.affiliation: Dipartimento Farmaco-Chimico, Università degli Studi di Bari, Via E. Orabona 4, 70125 Bari, Italy. nmargiotta@farmchim.uniba.it <nmargiotta@farmchim.uniba.it>
authors.forename: Nicola
authors.initials: N
authors.lastname: Margiotta
authors.forename: Giovanni
authors.initials: G
authors.lastname: Natile
authors.forename: Francesco
authors.initials: F
authors.lastname: Capitelli
authors.forename: Francesco P
authors.initials: FP
authors.lastname: Fanizzi
authors.forename: Angelina
authors.initials: A
authors.lastname: Boccarelli
authors.forename: Pietro
authors.initials: P
authors.lastname: De Rinaldis
authors.forename: Domenico
authors.initials: D
authors.lastname: Giordano
authors.forename: Mauro
authors.initials: M
authors.lastname: Coluccia
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D018360:Crystallography, X-Ray / Q000379:methods; D003596:Cytosine / Q000737:chemistry*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D045325:HCT116 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010984:Platinum / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D010984:Platinum; D003596:Cytosine; D002945:Cisplatin