Starting with 5-iodo-2'-deoxyuridine, a series of 5-alkynyl-2'-deoxyuridines (with n-propyl, cyclopropyl, 1-hydroxycyclohexyl, p-tolyl, p-tert-butylphenyl, p-pentylphenyl, and trimethylsilyl alkyne substituents) have been synthesized via the palladium-catalyzed (Sonogashira) coupling reaction followed by a simplified isolation protocol (76-94% yield). The cytotoxic activity of modified nucleosides against MCF-7 and MDA-MB-231 human breast cancer cells has been determined in vitro. 5-Ethynyl-2'-deoxyuridine, the only nucleoside in the series containing a terminal acetylene, is the most potent inhibitor with IC 50 (μM) 0.4 ± 0.3 for MCF-7 and 4.4 ± 0.4 for MDA-MB-231.
The 5-endo-dig chlorocyclization of 1,4-disubstituted alk-3-yn-1-ones (propargylic ketones) with the use of trichloro-striazinetrione (trichloroisocyanuric acid, TCCA; 0.4 equiv.) in toluene, at room temperature, in the absence of base, provides 2,5-disubstituted 3-chlorofurans in high yields (79-96 %). The reaction can be accomplished by using commercially available swimming pool sanitizer. Selected 3-chlo-
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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.