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 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.

Platinum complexes with imino ethers or cyclic ligands mimicking imino ethers: synthesis, in vitro antitumour activity, and DNA interaction properties.

Both trans- and cis-[PtCl(2)(NH(3))(L)] compounds have been synthesized, L representing either the imino ether HN=C(OMe)Me having a Z or E configuration at the C=N double bond, or the cyclic ligands N = C(OMe)CH2CH2CH2 and N = C(Me)OCH2CH2 (compounds 1-4 for trans geometry and 5-8 for cis geometry, respectively). The cyclic ligands mimic the imino ether ligands but, differently from imino ethers, cannot undergo change of configuration. In a panel of human tumor cells, trans compounds inhibit growth much more than transplatin. Moreover, compound 1 in most cases is less active than 2, and 1 and 2 are less active than 3 and 4, respectively. For cis compounds with imino ethers, the activity is reduced (5) or unaffected (6) with respect to cisplatin. Moreover, unlike trans compounds, substitution of cyclic ligands (7,8) for imino ethers (5,6) generally decreases the activity. This determines, for compounds with cyclic ligands, an unusual inversion of the cis geometry requirement for activity of platinum(II) species. Importantly,1-4 and 5-8 partially circumvent the multifocal cisplatin resistance of A2780cisR cells, and 1-4 also overcome resistance from reduced uptake of 41McisR cells. DNA interaction regioselectivity of 1-4 and 5-8 is not substantially modified with respect to transplatin and cisplatin. However, both imino ethers and cyclic ligands slow down the DNA interstrand cross-link reaction, ( E)-HN=C(OMe)Me and N = C(Me)OCH2CH2 decreasing also its extent. Therefore, DNA interaction of 1-4 and 5-8 appears to be characterized by persistent monoadducts (1-4), and by monoadducts and/or intrastrand cross-links structurally different from those of cisplatin (5-8). This study demonstrates that ligand configuration modulates the activity of both trans and cis compounds, and supports the development of platinum drugs based on their coordination chemistry to combat cisplatin resistance.

Neutrophil recruitment and airway epithelial cell involvement in chronic cystic fibrosis lung disease.

The pathological hallmark of cystic fibrosis (CF) chronic inflammatory response is the massive neutrophil influx into the airways. This dysregulated neutrophil emigration may be caused by the abnormal secretion of chemoattractants by respiratory epithelial cells and polarised lymphocyte T-helper response. Neutrophils from CF patients have a different response to inflammatory mediators than neutrophils from normal subjects, indicating that they are primed in vivo before entering the CF airways. CF neutrophils secrete more myeloperoxidase and elastase, mobilise less opsonin receptors and release less L-selectin than non-CF neutrophils. Moreover, they show altered cytokine production and a dysregulated chemotaxis response. Laboratory studies now suggest that CFTR is involved in regulating some neutrophil functions and indicate that altered properties of CF neutrophils may depend on genetic factors. Current gene therapy approaches are targeted to the respiratory epithelium, but many hurdles oppose an efficient and efficacious CFTR gene transfer. The possibility of CFTR gene therapy-based approach targeting CF neutrophils at the hematopoietic stem cell level is discussed.