Systematic differences in electrochemical reduction of the structurally characterized anti-cancer platinum(IV) complexes [Pt{((p-HC6F4)NCH2)2}-(pyridine)2Cl2], [Pt{((p-HC6F4)NCH2)2}(pyridine)2(OH)2], and [Pt{((p-HC6F4)NCH2)2}(pyridine)2(OH)Cl]

Abstract

The putative platinum(IV) anticancer drugs, [Pt{((R)NCH2)2}(py)2XY] (X,Y = Cl, R = p-HC6F4 (1a), C6F5 (1b); X,Y = OH, R = p-HC6F4 (2); X = Cl, Y = OH, R = p-HC6F4 (3), py = pyridine) have been prepared by oxidation of the PtII anticancer drugs [Pt{((R)NCH2)2}(py)2] (R = p-HC6F4 (4a) or C6F5 (4b)) with PhICl2 (1a,b), H2O2 (2) and PhICl2/Bu4NOH (3). NMR spectroscopy and the X-ray crystal structures of 1b, 2 and 3 show that they have octahedral stereochemistry with the X,Y ligands in the trans-position. The net two electron electrochemical reduction of 1a, 2 and 3 has been studied by voltammetric, spectroelectrochemical and bulk electrolysis techniques in acetonitrile. NMR and other data reveal that reduction of 1a gives pure 4a via the elimination of both axial chloride ligands. In the case of 2, one end of the diamide ligand is protonated and the resulting -NH(p-HC6F4) group dissociated giving a [Pt{N(p-HC6F4)CH2CH2NH(p-HC6F4)}] arrangement, one pyridine ligand is lost and a hydroxide ion retained in the coordination sphere. Intriguingly, in the case of reduction of 3, a 50% mixture of the reduction products of pure 1a and 2 is formed. The relative ease of reduction is 1 > 3 > 2. Testing of 1a, 2 and 3 against L1210 and L1210(DDP) (DDP = cis-diamine-dichloroplatinum(II)) mouse leukaemia cells shows all to be cytotoxic with IC50 values of 1.0-3.5 μM. 2 and 3 are active in vivo against AHDJ/PC6 tumor line when delivered in peanut oil despite being hard to reduce electrochemically, and notably are more active than 4a delivered in this medium whilst comparable with 4a delivered in saline/Tween.