Pyrimidinylpropenamides as antitumor agents. Analogues of the antibiotic sparsomycin.
A series of pyrimidinylpropenamides 9 and their oxidation products 10 was prepared, as analogues of sparsomycin (1), for antitumor evaluation. Syntheses involved condensation of the appropriate amino alcohol 5 with acid 8. The resulting sulfides 9 were then oxidized with NaIO4 or H2O2 to sulfoxides 10. Activity was studied in lymphocytic leukemia P-338 and KB cell culture. With the exception of the n-decyl analogue, all of the deoxygenated compounds 9 were inactive regardless of the stereochemical form. In the sulfoxide series 10, those compounds prepared with an L configuration at the asymmetric carbon were also inactive. The completely racemic sulfoxides, on the other hand, displayed substantial antitumor activity (ILS = 37-61% in P-388; ED50 = 1.2-2.4 mug/ml in KB) suggesting that both the presence of a sulfoxide moiety and a D configuration at the chiral carbon atom were structural requirements for a positive antitumor response. There appeared to be a large tolerance for the group substituted at the sulfoxide moiety, however.
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis*; D002478:Cells, Cultured; D007942:Leukemia, Experimental / Q000503:physiopathology; D007945:Leukemia, Lymphoid / Q000503:physiopathology; D008722:Methods; D008938:Mitosis / Q000187:drug effects; D013033:Sparsomycin / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000903:Antibiotics, Antineoplastic; D013033:Sparsomycin