DNA interactions of monofunctional organometallic osmium(II) antitumor complexes in cell-free media

Publikace: JOURNAL OF MEDICINAL CHEMISTRY 51, 3635-3643 Autoři: Kostrhunova, H., Florian, J., Novakova, O., Peacock, AFA., Sadler, PJ., Brabec, V. Rok: 2008

Abstrakt

This work is the first in-depth study of osmium binding to DNA and confirms the pharmacological activity of a new class of anticancer metallodrugs. We investigated the interactions between the potential biological target DNA and four osmium(II) arene complexes, of the type [(eta(6)-arene)Os(LL)Cl](n+), where arene = biphenyl or p-cymene and LL = ethylenediamine, picolinate, or oxinate in an effort to understand their mechanism of action. Most notably. we show that these complexes bind to DNA. DNA adducts of the Os-II complexes that exhibit promising cytotoxic effects in ovarian tumor cell lines largely distort its conformation. The data are consistent with DNA binding of the complexes containing biphenyl as the arene ligand that involves combined coordination to guanine residues and noncovalent interactions between the arene ligand and DNA. The results also indicate both a mechanism of action and a detoxification mechanism for Os-II arene compounds different from those of cisplatin.