Metal-Based Paullones as Putative CDK Inhibitors for Antitumor Chemotherapy

Paullones constitute a class of potent cyclin-dependent kinase inhibitors. To overcome the insufficient solubility and bioavailability, which hamper their potential medical application, we aim at the development of metal-based derivatives. Two types of paullone ligands, L¹–L³ and L⁴, with different locations of metal-binding sites, were prepared. They were found to form organometallic complexes of the general formula [M^IICl(η⁶-p-cymene)L]Cl (1–4, L = L¹–L⁴; a, M = Ru; b, M = Os). The complexes were characterized by X-ray crystallography, one- and two-dimensional NMR spectroscopy and other physical methods. Complexes 1–3, with a coordinated amidine unit, were found to undergo E/Z isomerization in solution. The reaction was studied by NMR spectroscopy, and activation parameters ΔH^‡ and ΔS^‡ were determined. Antiproliferative activity in the low micromolar range was observed in vitro in three human cancer cell lines by means of MTT assays. ³H-Thymidine incorporation assays revealed the compounds to lower the rate of DNA synthesis, and flow cytometric analyses showed cell cycle arrest mainly in G₀/G₁ phase.