Synthesis and biological evaluation of 6-ethynyluracil, a thiol-specific alkylating pyrimidine

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Abstract
6-Ethynyluracil (3) was prepared by 2 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 Pd/Cu 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-Cy, but did not react with Gly or L-Lys. 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 [mouse] leukemia L1210, [mouse] B-16 melanoma, and [mouse] Lewis lung carcinoma cells at concentrations ranging from 1 .times. 10-6 to 2 .times. 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.

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