Metallo-nucleosides: synthesis and biological evaluation of hexacarbonyl dicobalt 5-alkynyl-2'-deoxyuridines.
Reactions of 5-alkynyl-2'-deoxyuridines with dicobalt octacarbonyl Co2(CO)8 in THF at room temperature gave hexacarbonyl dicobalt nucleoside complexes (77-93%). The metallo-nucleosides were characterized, including an X-ray structure of a 1-cyclohexanol derivative. In crystalline form, the Co-Co bond is perpendicular to the plane of the uracil base, which is found in the anti position. The level of growth inhibition of MCF-7 and MDA-MB-231 human breast cancer cell lines was examined and compared to results obtained with the alkynyl nucleoside precursors. The cobalt compounds displayed good antiproliferative activities with IC50 values in the range of 5-50 microM. Interestingly, the coordination of the dicobalt carbonyl moiety to 5-alkynyl-2'-deoxyuridines led to a significant increase in the cytotoxic potency for alkyl/aryl substituents at the non-nucleoside side of the alkyne, but in the case of hydrogen (terminal alkyne) or a silyl group, a decrease of the cytotoxic effect was observed. As demonstrated using examples for an active and a low active target compound, the cytotoxicity was significantly influenced by the uptake into the tumor cells and the biodistribution into the nuclei.
Sergeant
Craig D
CD
Department of Chemistry and Center for Biomedical Research, Oakland University, 2200 N. Squirrel Rd., Rochester, Michigan 48309-4477, USA.
Ott
Ingo
I
Sniady
Adam
A
Meneni
Srinivasarao
S
Gust
Ronald
R
Rheingold
Arnold L
AL
Dembinski
Roman
R
D000480:Alkynes / Q000737:chemistry*; D045744:Cell Line, Tumor; D002467:Cell Nucleus; D049109:Cell Proliferation / Q000187:drug effects; D003035:Cobalt / Q000737:chemistry*; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D014529:Uridine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity
D000480:Alkynes; D009942:Organometallic Compounds; D003035:Cobalt; D014529:Uridine