Metal-based Paullones as putative CDK inhibitors for antitumor chemotherapy

Author(s)

Wolfgang Schmid, Roland John, Gerhard Mühlgassner, Petra Heffeter, Michael Jakupec, Mathea Sophia Galanski, Walter Berger, Bernhard Keppler, Vladimir Arion

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, 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(?6-p-cymene)L]Cl (1-4, L = L1-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 ?H¿ and ?S ¿ 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. © 2007 American Chemical Society.

Organisation(s)

Department of Inorganic Chemistry

External organisation(s)

Medizinische Universität Wien

Journal

Journal of Medicinal Chemistry

Volume

50

Pages

6343-6355

No. of pages

13

ISSN

0022-2623

Publication date

2007

Peer reviewed

Yes

Austrian Fields of Science 2012

104003 Inorganic chemistry

Sustainable Development Goals

SDG 3 - Good Health and Well-being

Portal url

https://ucrisportal.univie.ac.at/en/publications/d7075da0-05a8-43ad-b248-79164978c346