Photocytotoxic trans-diam(m)ine platinum(IV) diazido complexes more potent than their cis isomers.

The photocytotoxicity of a series of anticancer trans-dihydroxido [Pt(N(3))(2)(OH)(2)(NH(3))(X)] (X = alkyl or aryl amine) platinum(IV) diazido complexes has been examined, and the influence of cis-trans isomerism has been investigated. A series of photoactivatable Pt(IV)-azido complexes has been synthesized: The synthesis, characterization, and photocytotoxicity of six mixed-ligand ammine/amine Pt(IV) diazido complexes, cis,trans,cis-[Pt(N(3))(2)(OH)(2)(NH(3))(X)] where X = propylamine (4c), butylamine (5c), or pentylamine (6c) and aromatic complexes where X = pyridine (7c), 2-methylpyridine (8c), or 3-methylpyridine (9c) are reported. Six all-trans isomers have also been studied where X = methylamine (2t), ethylamine (3t), 2-methylpyridine (8t), 4-methylpyridine (10t), 3-methylpyridine (9t), and 2-bromo-3-methylpyridine (11t). All of the complexes exhibit intense azide-to-Pt(IV) LMCT bands (ca. 290 nm for trans and ca. 260 nm for cis). When irradiated with UVA light (365 nm), the Pt(IV) complexes undergo photoreduction to Pt(II) species, as monitored by UV-vis spectroscopy. The trans isomers of complexes containing aliphatic or aromatic amines were more photocytotoxic than their cis isomers. One of the cis complexes (9c) was nonphotocytotoxic despite undergoing photoreduction. Substitution of NH(3) ligands by MeNH(2) or EtNH(2) results in more potent photocytotoxicity for the all-trans complexes. The complexes were all nontoxic toward human keratinocytes (HaCaT) and A2780 human ovarian cancer cells in the dark, apart from the 3-methylpyridine (9t), 2-bromo-3-methylpyridine (11t), and 4-methylpyridine (10t) derivatives.

Reactions of PtII diamine anticancer complexes with trypanothione and octreotide.

The products formed in reactions of the square-planar platinum(II) anticancer complexes, [Pt(en)Cl(2)] and [Pt(R,R-dach)Cl(2)] where en=ethylenediamine and dach=diaminocyclohexane, with trypanothione, a glutathione analogue found in some parasites, and octreotide, a synthetic analogue of the hormone somatostatin, have been investigated. Mononuclear and binuclear platinum adducts were formed in reactions of the cyclic disulfides in their oxidised and reduced forms, and were analysed by UV-visible spectroscopy and liquid chromatography-mass spectrometry (LC-MS). NMR and molecular modelling studies were carried out on the mononuclear adducts.

Palladium(II) diamine complex induces reduction of glutathione disulfide.

Reaction of [Pd(1R,2R-diaminocyclohexane)Cl(2)] with the oxidised form of the tripeptide glutathione ([gamma]-l-glutamyl-l-cysteinyl-glycine) in aqueous solution leads to reductive cleavage of the disulfide bond.

Investigations into the interactions between DNA and conformationally constrained pyridylamineplatinum(II) analogues of AMD473.

The syntheses of [PtCl(2)(amp)] (amp = 2-pyridylmethylamine) and enantiomerically pure [PtCl(2)(R-pea)] and [PtCl(2)(S-pea)] (pea = 1-(2-pyridyl)ethylamine) and the crystal structure of [PtCl(2)(R-pea)] are reported. The reactions of [PtCl(2)(amp)] and of the enantiomers of [PtCl(2)(pea)] with d(GpG) and with a 52-base-pair oligonucleotide were investigated. Each of the reactions with d(GpG) resulted in the formation of three platinated bifunctional d(GpG) species in a ratio of 1:2:1. These species were shown to be a pair of isomers, one of which exists as a pair of slowly interconverting rotamers that can be separated by HPLC but reequilibrate after 5 days at 37 degrees C. The pyridyl moieties of the pyridylalkylamine ligands are constrained to lie in the coordination plane, and as a consequence, the rotation about the Pt-N7 bond of the adjacent guanine is highly restricted. 2D NMR investigations were carried out on the isomer of [Ptd(GpG)(amp)] that did not form separable rotamers and identified it as the isomer having the pyridine adjacent to the 5'-guanine of the d(GpG). The reaction of each of the three [PtCl(2)(py-R)] complexes (py-R = amp or pea) with a 52-base-pair oligonucleotide resulted in the formation of the same three bifunctional d(GpG) adducts in approximately the same ratios as the reactions with d(GpG), indicating that negligible stereoselectivity results from interactions between the complexes and duplex DNA.

Stereospecificity and enantioselectivity in the binding of the platinum(II) complex [PtCl2(tmdz)] (tmdz = 5,5,7-trimethyl-1,4-diazacycloheptane) to dinucleotides and oligonucleotides.

The two stereoisomers formed on reaction of each of the enantiomers of [PtCl2(tmdz)] with d(GpG) have been identified by using one- and two-dimensional 1H NMR spectroscopy. For both isomers formed with the R enantiomer the 3'-H8 shifts are downfield from those for the 5'-H8. For the S enantiomer the reverse is observed, showing that the bulky tmdz ligand determines the pattern of shifts. Models of these isomers generated by molecular mechanics show that the bulky tmdz ligand limits the rotation of the guanine bases and enforces right-handed (R2) canting for both isomers formed by the R enantiomer and left-handed (L1) canting for those formed by the S enantiomer. The pattern of H8 shifts is the opposite to that expected for these cantings; this suggests that other factors may play a role in determining these shifts. The interactions between the tmdz and d(GpG) ligands are also shown by molecular mechanics and the broadness of the H8 NMR signals to influence the tendency of the coordinated guanine bases to rotate about their Pt-N7 bonds. Reaction of each of the enantiomers with a 52 base-pair nucleotide, with a total of six GpG binding sites, resulted in the formation of only one of the stereoisomers in each case, the first reported case of complete stereoselectivity, or stereospecificity, in the reaction of Pt complexes with DNA. The observed stereoisomers were identified by comparison with the properties of the d(GpG) complexes. Molecular mechanics models of the adducts with duplex DNA show that the nonformation of one stereoisomer is consistent with the steric bulk of the tmdz ligand preventing closure from the monofunctional adduct to the bifunctional adduct. Enantioselectivity is also observed in that the R enantiomer forms more monofunctional adducts than bifunctional (59:41), whereas the S enantiomer forms more bifunctional adducts (27:73). The origins of this enantioselectivity must be at the level of monofunctional adduct formation and this has been investigated by molecular mechanics modelling.