Cellular accumulation, lipophilicity and photocytotoxicity of diazido platinum(IV) anticancer complexes.
The lipophilicity of ten photoactivatable platinum(IV) diazido prodrugs of formula trans,trans,trans-[Pt(N3 )2 (OH)2 (R)(R')] (where R and R' are NH3 , methylamine, ethylamine, pyridine, 2-picoline, 3-picoline or thiazole) has been determined by their retention times on reversed-phase HPLC. The lipophilicity of the complexes shows a linear dependence on the lipophilicity (partition coefficient) of the ligands. Accumulation of platinum in A2780 human ovarian cancer cells after one hour drug exposure in the dark is compared with their cytotoxic potency on activation with UVA (365 nm) and to their lipophilicity. No correlation between lipophilicity and intracellular accumulation of platinum was observed, perhaps suggesting involvement of active transport and favoured influx of selected structures. Furthermore, no correlation between platinum accumulation and photocytotoxicity was observed in A2780 cancer cells, implying that the type of intracellular damage induced by these complexes plays a key role in their cytotoxic effects.
Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL (UK); IMDEA Nanoscience, C/ Faraday 9, Cantoblanco, 28049 Madrid (Spain).
Ana M
AM
Pizarro
Ruth J
RJ
McQuitty
Fiona S
FS
Mackay
Yao
Y
Zhao
Julie A
JA
Woods
Peter J
PJ
Sadler
D000588:Amines / Q000737:chemistry; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002851:Chromatography, High Pressure Liquid; D002945:Cisplatin / Q000737:chemistry / Q000633:toxicity; D056831:Coordination Complexes / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D006801:Humans; D007536:Isomerism; D010847:Picolines / Q000737:chemistry; D010984:Platinum / Q000737:chemistry*; D013844:Thiazoles / Q000737:chemistry; D014466:Ultraviolet Rays
D000588:Amines; D000970:Antineoplastic Agents; D056831:Coordination Complexes; D010847:Picolines; D013844:Thiazoles; D010984:Platinum; D002945:Cisplatin
anticancer agents; cell uptake; lipophilicity; metallodrugs; photocytotoxicity; platinum drugs