Barnett Rosenberg's serendipitous discovery of cisplatin, the most celebrated inorganic medicinal agent to date, derives from the unanticipated in situ oxidation of metallic Pt(0) electrodes in an ammonium chloride-containing E.coli growth medium to generate cytotoxic Pt(II) species. The impact of Rosenberg's fundamental discovery has fueled the development of second-generation compounds while also stimulating investigations into complexes bearing alternative structural compositions (trans-Pt(II) and Pt-phosphine complexes) and/or alternative cytotoxicity mechanisms. Our previous work with complexes bearing reactive radical-generating enediyne ligands has identified that metals may be used to control enediyne conformations and consequently, reactivities towards Bergman cyclization. Comparatively, tetrahedral metalloenediynes are markedly more stable to cyclization than their planar counterparts. In light of this, metal-based redox chemistry is used to rapidly and efficiently switch these stable constructs to reactive molecules capable of Bergman cyclization via a chemical rendering of Rosenberg's original Pt-electrode oxidation. We have demonstrated that addition of a mild oxidant to a thermally robust tetrahedral Pt(0)-phosphine metalloenediyne leads to the instantaneous generation of a Pt(II) complex which, after ligand substitution, yields a square planar complex that cyclizes spontaneously at ambient temperature to afford a cis-Bergman cyclized Pt(II) product. Redox activated metalloenediynes such as this represent potential triggerable, dual-action therapeutics due to coupling of the reactive diradical intermediate capable of H-atom abstraction with the DNA crosslinking potential via the square planar product. As an extension of this work, we have expanded the ligand suite to explore the effects of ligand sterics and electronics on the oxidation and cyclization mechanism of these metalloenediynes. Additionally, we have investigated other stable metalloenediyne constructs (geometries and/or metal centers) to assess the viability of this metal-based redox triggering mechanism as a general method for enediyne activation.

Redox-mediated Bergman cyclization: Towards the development of dual-action metalloenediyne therapeutics

246th National Meeting (2013)

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