Metal-Based Paullones as Putative CDK Inhibitors for Antitumor Chemotherapy

Journal of Medicinal Chemistry
2007.0

Abstract

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, L (1) - L (3) and L (4) , with different locations of metal-binding sites, were prepared. They were found to form organometallic complexes of the general formula [M (II)Cl(eta (6)- p-cymene)L]Cl ( 1- 4, L = L (1) - L (4) ; 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 Delta H (double dagger) and Delta S (double dagger) were determined. Antiproliferative activity in the low micromolar range was observed in vitro in three human cancer cell lines by means of MTT assays. (3)H-Thymidine incorporation assays revealed the compounds to lower the rate of DNA synthesis, and flow cytometric analyses showed cell cycle arrest mainly in G 0/ G 1 phase.

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