DNA interactions of monofunctional organometallic osmium(II) antitumor complexes in cell-free media.
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 OsII 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 OsII arene compounds different from those of cisplatin.
Kostrhunova
Hana
H
Institute of Biophysics, Academy of Sciences of the Czech Republic, vvi, Královopolská 135, CZ-61265 Brno, Czech Republic.
Florian
Jakub
J
Novakova
Olga
O
Peacock
Anna F A
AF
Sadler
Peter J
PJ
Brabec
Viktor
V
D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism*; D045744:Cell Line, Tumor; D002474:Cell-Free System; D002945:Cisplatin / Q000737:chemistry; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D018736:DNA Adducts / Q000737:chemistry; D004278:DNA, Superhelical / Q000737:chemistry; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004996:Ethidium; D005456:Fluorescent Dyes; D006801:Humans; D007364:Intercalating Agents; D008968:Molecular Conformation; D009841:Oligonucleotides / Q000737:chemistry; D009942:Organometallic Compounds / Q000737:chemistry / Q000378:metabolism*; D009992:Osmium; D013050:Spectrometry, Fluorescence; D013329:Structure-Activity Relationship; D044366:Transition Temperature
D000970:Antineoplastic Agents; D018736:DNA Adducts; D004278:DNA, Superhelical; D005456:Fluorescent Dyes; D007364:Intercalating Agents; D009841:Oligonucleotides; D009942:Organometallic Compounds; D009992:Osmium; D004247:DNA; C427203:calf thymus DNA; D004996:Ethidium; D002945:Cisplatin