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 [MIICl(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.