Metallo-nucleosides: synthesis and biological evaluation of hexacarbonyl dicobalt 5-alkynyl-2′-deoxyuridines

Abstract

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.

Cleavage of Functionalized DNA Containing 5‐Modified Pyrimidines by Type II Restriction Endonucleases

“…The spectral data were in accordance with the literature. [25] 5-Ethynyl-2'-deoxycytidine (dC E ) yield: 74 %. The spectral data were in accordance with the literature.…”

The Synthesis, Structure, and FTIR Spectroelectrochemistry of W(CO)5 Complexes of 4‐Oxo‐4‐(2,5‐dimethylazaferrocen‐1′‐yl)butanoic and 5‐Oxo‐5‐(2,5‐dimethylazaferrocen‐1′‐yl)pentanoic Acids

“…The NMR spectra were recorded with Bruker AV400 (400 MHz) and Varian Gemini 200BB (200 MHz) spectrometers. Chemical shifts are reported in δ (ppm) using residual CHCl 3 ( 1 H δ = 7.26 ppm) as the reference. Mass spectra were recorded using EI methods with a Finnigan MAT 710A spectrometer and ESI methods using a Varian 500MS LC spectrometer.…”

“…It has been demonstrated, for exam-ple, that tricarbonyliron complexes of nucleosides exhibit significant apoptosis-inducing properties, [2] whereas hexacarbonyldicobalt deoxyuridines display good antiproliferative activities toward human breast cancer cell lines. [3] An acetylenehexacarbonyldicobalt complex of o-acetylsalicylic acid has been recognized as an effective cyclooxygenase (COX) enzymes inhibitor, [4] and selected indocarbazole carbonyl ruthenium complexes were recognized as effective glycogen synthase kinase 3 inhibitors. [5] Hexacarbonyldicobalt derivatives of the neuropeptide leucine-enkephalin have also been described and represent the first organometallic peptide bioconjugates to exhibit significant toxicity against two different tumor cell lines.…”

Alkyne hexacarbonyl dicobalt complexes in medicinal chemistry and drug development

“…Interestingly, in this study, the later to be lead structure of cytotoxic hexacarbonyl dicobalt complexes, a derivative containing a ligand derived from acetylsalicylic acid (Co-ASS; see figure 6), was described for the first time. These results triggered more intensive research into the use of hexacarbonyl dicobalt complexes against cancerous diseases [24,[28][29][30][31][32][33] . The most striking finding of the following investigations was the fact that minor modifications of the ligand structure of the lead compound Co-ASS led to significantly decreased antiproliferative effects.…”