Synthesis and antitumor evaluation of alpha-methylene-gamma-butyrolactone-linked to 5-substituted uracil nucleic acid bases

Six, heretofore undescribed, 5'-Methyl-5'-(5-Substituted uracil-1-ylmethyl)-2'-oxo-3'-methylenetetrahydrofurans (F, Cl, Br, I, CH3, H) (6a-f) were synthesized and evaluated against three cell lines (FM-3A, P-388 and U-937). For the preparation of alpha-methylene-gamma-butyrolactone bearing 5-substituted uracils (6a-f), the efficient Reformatsky type reaction was employed which involves the treatment of ethyl alpha-(bromomethyl) acrylate and zinc with the respective 5-substituted uracil-1-ylacetones (5a-f). The acetone derivatives (5a-f) were directly obtained by the respective alkylation reaction of 5-substituted uracils with chloroacetone in the presence of K2CO3 (or NaH). These lactone compounds 6a-f exhibited moderate to significant activity in all of the three cell lines, and 6b, 6c and 6e showed significant antitumor activities (inhibitory concentrations (IC50) ranged from 1.3-3.8 mu g/ml).