Synthesis and biological evaluation of 6-ethynyluracil, a thiol-specific alkylating pyrimidine.
6-Ethynyluracil (3) was prepared by two different synthetic procedures. In one approach, 6-formyluracil was reacted with (dibromomethylene)triphenylphosphorane to give 6-(2,2-dibromovinyl)uracil (2), which was silylated and treated with phenyllithium to yield 3. Alternatively, silylated 6-iodouracil was reacted with trimethylsilylacetylene in dry triethylamine in the presence of a palladium/copper catalyst to give 6-[(trimethylsilyl)ethynyl]uracil (5). Compound 5 was converted to 3 in refluxing methanol. At neutral pH, 3 reacted with thiols, such as glutathione, 2-mercaptoethanol, and L-cysteine, but did not react with glycine or L-lysine. This reaction was accompanied by a shift in the UV maximum of 3 from 286 nm to 321-325 nm. The reaction of 3 with 2-mercaptoethanol gave cis-6-[2[(2-hydroxyethyl)-thio]vinyl]uracil as the predominant product. Compounds 2 and 3 inhibited the growth of leukemia L1210, B-16 melanoma, and lewis lung carcinoma cells at concentrations ranging from 1 x 10(-6) to 2 x 10(-5) M. As determined with L1210 cells, the inhibition of growth caused by 2 and 3 was not prevented by the natural pyrimidines, indicating that the agents do not act as antimetabolites.
D000477:Alkylating Agents / Q000138:chemical synthesis*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D002478:Cells, Cultured; D055598:Chemical Phenomena; D002621:Chemistry; D007939:Leukemia L1210 / Q000188:drug therapy; D008545:Melanoma / Q000188:drug therapy; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
D000477:Alkylating Agents; D000970:Antineoplastic Agents; D014498:Uracil; C036158:6-ethynyluracil