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Various(E)-ƒÀ-(pyrimidin-5-yl)acrylamides(4 and 5)were synthesized as sparsomycin analogs, and the relationship between chemical structure and antitumor activity was examined.Synthesis involved condensation of appropriate acids(3)and methyl methioninate(L and D isomers)by the mixed anhydride method using isobutyl chlorocarbonate.The antitumor activity was studied by [methyl-3H]thymidine incorporation assay with mouse leukemia L5178Y cells in vitro.The concentrations in ƒÊg/ml required for 50% inhibition of incorporation by compounds 4b,4f,g,5b, and 5f,g,which have no substituent at the 2 or 6 position on pyrimidine ring,were particularly high.Thus, such substituents enhanced antitumor activity,although the activity was almost uninfluenced by changes of the alkoxy group as a substituent. (E)-ƒÀ-(pyrimidin-5-yl) acrylamide; antitumor activity Sparsomycin(1)is a metabolite of Streptomyces sparsogenes2)and S.cuspidosporus.3) Many years were required for its structure determination because of some unique features (Fig.1).4)Although this compound exhibits a wide range of biological activities,3,5)the most interesting biological activity was its antitumor activity,which appears to be primarily due to inhibition of protein synthesis by blocking the peptidyl transferase function of the larger ribosomal subunit6)Sparsomycin has attracted widespread attention from the viewpoint of possible clinical application,but its severe eye toxicity7)has limited its usefulness in cancer chemotherapy.Therefore several studies dealing with the synthesis of sparsomycin analogs have been made8-13)with the aim of eliminating its toxicity and clarifying the structure-activity relationship of sparsomycin. We have also synthesized many analogs of sparsomycin and tested their biological activities.1,14)In a preliminary report,1)we showed that O-methylation of the pyrimidine ring remarkably enhanced the antitumor activity in vitro of these analogs.The present paper describes the preparation of O-alkoxy derivatives of(E)-ƒÀ-(pyrimidin-5-ypacrylamides,which have various substitution patterns on the pyrimidine ring,and also an extended study of the structural and stereochemical requirements for their antitumor activity against mouse leukemia cells in vitro.

Sparsomycin analogs. V. Synthesis and antitumor activity of (E)-.BETA.-(pyrimidin-5-yl)acrylamides.