Photoactivatable Platinum Complexes

Abstract

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. Based on the knowledge of Pt(IV) photochemistry, Pt(IV) analogs of cisplatin, [Pt(en)Cl(2)] and transplatin were designed, synthesized and investigated for their ability to be photoreduced to cytotoxic Pt(II) species. Two classes of photoactivatable Pt complexes have been looked at thus far: diiodo-Pt(IV) and diazido-Pt(IV) diam(m)ine complexes. The first generation, diiodo-Pt(IV) complexes, represented by cis, trans-[Pt(en)(I)(2)(OAc)(2)], react to visible light by binding irreversibly to DNA and forming adducts with 5'-GMP in the same manner as [Pt(en)Cl(2)]. Furthermore, the photolysis products are cytotoxic to human cancer cells in vitro. However, these complexes are too reactive towards biological thiols (i.e., glutathione), which rapidly reduced them to cytotoxic Pt(II) species, thus making them unsuitable as drugs. The second generation, diazido-Pt(IV) complexes, represented by cis, trans, cis-[Pt(N(3))(2)(OH)(2)(NH(3))(2)] and cis, trans-[Pt(en)(N(3))(2)(OH)(2)], are also photosensitive, binding irreversibly to DNA and forming similar products with DNA and 5'-GMP in the presence of light as the respective Pt(II) complexes. However, they are stable to glutathione and thus show very low dark cytotoxicity. Light of lambda(irr) = 366 nm activates both complexes to cytotoxic species that effectively kill cancer cells by destroying their nuclei, leaving behind shrunken cell ghosts. Interestingly, the all-trans analog, trans, trans, trans-[Pt(N(3))(2)(OH)(2)(NH(3))(2)] is non-toxic to HaCaT keratinocytes in the dark, but as active as cisplatin in the light. These studies show that photoactivatable Pt(IV) antitumor agents represent a promising area for new drug development.

A potent cytotoxic photoactivated platinum complex

“…Such stability is important for a potential photochemotherapeutic agent, so that it can reach target sites before photoactivation. Two of the main photoproducts from irradiation of aqueous 15 2 ] 2ϩ is difficult to produce from reactions of transplatin under normal conditions in aqueous solution because the second hydrolysis step is very slow (22). This finding correlates with the scarcity of interstrand cross-links involving coordination of two G bases in trans positions for trans Pt II diam-(m)ine complexes (23), and with the inactivity of transplatin.…”

“…All experiments were carried out in a specially adapted photobiology laboratory, with ambient light levels Ͻ1 lux (Solatell). Cells were seeded at a density of Ϸ7 ϫ 10 4 cells per cm 2 and left to adhere overnight. After washing cells with PBS, test compounds were added in Earle's solution and incubated for 1 h (37°C/5% CO2).…”

“…To avoid these problems, we are exploring the use of inert, nontoxic platinum complexes that can be activated locally in cancer cells with light (2). In general, photoactivation offers potential for initiating unusual ligand substitution and redox reactions of transition metal complexes (3,4), and hence photoactivation may offer new mechanisms of anticancer activity.…”

Interactions of DNA with a New Platinum(IV) Azide Dipyridine Complex Activated by UVA and Visible Light: Relationship to Toxicity in Tumor Cells

“…Their activation with UVA irradiation to produce cytotoxic and reactive Pt II analogues does not require oxygen (1,2), an advantage over conventional photosensitizers currently used in photodynamic therapy (PDT), such as those based on tetrapyrrole derivatives. In addition, selective photoactivation of platinum complexes in cancer cells may help to overcome limitations connected with toxic side effects of antitumor platinum drugs currently used in the clinic.…”

Photoactivation of trans diamine platinum complexes in aqueous solution and effect on reactivity towards nucleotides

“…The photochemistry of the platinum complexes is of particular interest since light can induce a wide range of electronic transitions [14]. Photoactivable Pt IV -azide complexes represent a promising area for new drug development [15][16][17].…”