Cellular accumulation, lipophilicity and photocytotoxicity of diazido platinum(IV) anticancer complexes.

The lipophilicity of ten photoactivatable platinum(IV) diazido prodrugs of formula trans,trans,trans-[Pt(N3 )2 (OH)2 (R)(R')] (where R and R' are NH3 , methylamine, ethylamine, pyridine, 2-picoline, 3-picoline or thiazole) has been determined by their retention times on reversed-phase HPLC. The lipophilicity of the complexes shows a linear dependence on the lipophilicity (partition coefficient) of the ligands. Accumulation of platinum in A2780 human ovarian cancer cells after one hour drug exposure in the dark is compared with their cytotoxic potency on activation with UVA (365 nm) and to their lipophilicity.

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).

Synthesis, characterisation and photochemistry of Pt(IV) pyridyl azido acetato complexes.

Pt(II) azido complexes [Pt(bpy)(N(3))(2)] (1), [Pt(phen)(N(3))(2)] (2) and trans-[Pt(N(3))(2)(py)(2)] (3) incorporating the bidentate diimine ligands 2,2'-bipyridine (bpy), 1,10-phenanthroline (phen) or the monodentate pyridine (py) respectively, have been synthesised from their chlorido precursors and characterised by X-ray crystallography; complex 3 shows significant deviation from square-planar geometry (N(3)-Pt-N(3) angle 146.7 degrees ) as a result of steric congestion at the Pt centre. The novel Pt(IV) complexes trans, cis-[Pt(bpy)(OAc)(2)(N(3))(2)] (), trans, cis-[Pt(phen)(OAc)(2)(N(3))(2)] (), trans, trans, trans-[Pt(OAc)(2)(N(3))(2)(py)(2)] (), were obtained from via oxidation with H(2)O(2) in acetic acid followed by reaction of the intermediate with acetic anhydride.

A potent cytotoxic photoactivated platinum complex.

We show by x-ray crystallography that the complex trans, trans, trans-[Pt(N(3))(2)(OH)(2)(NH(3))(py)] (1) contains an octahedral Pt(IV) center with almost linear azido ligands. Complex 1 is remarkably stable in the dark, even in the presence of cellular reducing agents such as glutathione, but readily undergoes photoinduced ligand substitution and photoreduction reactions. When 1 is photoactivated in cells, it is highly toxic: 13-80 x more cytotoxic than the Pt(II) anticancer drug cisplatin, and ca.

Photoactivatable platinum complexes.

The development of photoactivatable prodrugs of platinum-based antitumor agents is aimed at increasing the selectivity and hence lowering toxicity of this important class of antitumor drugs. These drugs could find use in treating localized tumors accessible to laser-based fiber-optic devices. Pt(IV) complexes appeared attractive because these octahedral complexes are usually substitution inert and require reduction to the Pt(II) species to become cytotoxic.

Transplatin is cytotoxic when photoactivated: enhanced formation of DNA cross-links.

It is well-known that although cisplatin, [cis-[PtCl2(NH3)2], is an anticancer drug, its isomer transplatin is not cytotoxic. Here we show that transplatin is almost as cytotoxic as cisplatin when treated cells (human keratinocytes HaCaT and ovarian cancer A2780 cells) are irradiated with UVA light (50 min, 1.77 mW cm-2).

A photoactivated trans-diammine platinum complex as cytotoxic as cisplatin.

The synthesis and X-ray structure (as the tetrahydrate) of the platinum(IV) complex trans,trans,trans-[Pt(N(3))(2)(OH)(2)(NH(3))(2)] 3 are described and its photochemistry and photobiology are compared with those of the cis isomer cis,trans,cis-[Pt(N(3))(2)(OH)(2)(NH(3))(2)] 4. Complexes 4 and 3 are potential precursors of the anticancer drug cisplatin and its inactive trans isomer transplatin, respectively. The trans complex 3 is octahedral, contains almost linear azide ligands, and adopts a layer structure with extensive intermolecular hydrogen bonding.

Light-activated destruction of cancer cell nuclei by platinum diazide complexes.

A possible way to avoid dose-limiting side effects of platinum anticancer drugs is to employ light to cause photochemical changes in nontoxic platinum prodrugs that release active antitumor agents. This strategy could be used in the treatment of localized cancers accessible to irradiation (e.g.

Formation of platinated GG cross-links on DNA by photoactivation of a platinum(IV) azide complex.

Platinum(II) diam(m)ine complexes such as cisplatin are effective anticancer drugs but have accompanying side effects. We are exploring the design of platinum complexes with low toxicity that could be photoactivated selectively at the target site. We show here that the Pt(IV) azide complex cis, trans-[Pt(en)(N(3))(2)(OH)(2)] is unreactive towards DNA until irradiated with visible light.