The clinical use of the antineoplastic drugs: taxol, colchicine, vinca alkaloids, nocodazole and a number of related microtubule targeting drugs is based on their ability to induce cell death by disrupting the dynamics of polymerization and depolymerization of tubulin into microtubules (MTs) in cells. While most of these agents inhibit tubulin polymerization the taxanes were the first shown to act by inhibiting depolymerization the MTs. In this paper, we show that simple ruthenium polypyridyl complexes (RPCs), such as tris(4,7-diphenyl-1,10-phenanthroline)ruthenium(II) chloride (RPC2) not only inhibits MT depolymerization in vitro, but does so in live cells and induces cell death at doses as low as 3 μM. The action of RPC2 on MTs in live cells was visualized in real time by tracking fluorescently-tagged microtubule plus end–tracking proteins by microscopy. Calorimetric data reveals an associative binding constant of 4.8x10<sup>6</sup> M<sup>-1</sup> for RPC2 to pre-formed MTs showing surprisingly tight binding, and studies of the sub-cellular localization of the ruthenium in treated cells reveals over 85% is co-locallized with the cytoskeletal proteins. These data indicate that RPCs and related metal complexes may be a useful synthetically accessible platform by which to design microtubule targeting agents for therapeutic or other applications, as these RPCs are far simpler to synthesize than taxanes and the related complex organic molecules currently pursued as microtubule stabilizing agents.

Disruption of microtubule function in cultured human cells by a cytotoxic ruthenium(II) polypyridyl complex

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.