POTENTIAL ANTITUMOR ALPHA-METHYLENE-GAMMA-BUTYROLACTONE-BEARING NUCLEIC-ACID BASES .2. SYNTHESIS OF 5'-METHYL-5'-[2-(5-SUBSTITUTED IL-1-YL)ETHYL]-2'-OXO-3'-METHYLENETETRAHYDROFURANS

Ten, heretofore unreported, 5'-methyl-5'-[2-(5-substituted l-1-yl)ethy l)]-2'-oxo-3'-methylenetetrahydrofurans (H, F, Cl, Br, I, CH3, CF3, CH 2CH3, CH=CH2, SePh) (7a-j) were synthesized and evaluated against four cell lines (K-562, FM-3A, P-388 and U-937). For the preparation of al pha-methylene-gamma-butyrolactone-linked to 5-substituted uracils (7a- j), the convenient Reformasky type reaction was employed which involve s the treatment of ethyl alpha-(bromomethyl)acrylate and zinc with the respective 1-(5-substituted uracil-1-yl)-3-butanone (6a-j). The 5-sub stituted uracil ketones (6a-j) were directly obtained by the respectiv e Michael type reaction of vinyl methyl ketone with the K2CO3 (or NaH) -treated 5-substituted uracils (5a-j) in the presence of acetic acid i n the DMF solvent. The alpha-methylene-gamma-butyrolactone compounds s howing the most significant antitumor activity are 7e, 7f, 7h and 7j ( inhibitory concentration (IC50) ranging from 0.69 to 2.9 mu(g)/ml), wh ile 7b, 7g and 7i have shown moderate to significant activity. The com pounds 7a, 7c and 7d were found to be inactive. The synthetic intermed iate compounds 6a-j were also screened and found marginal to moderate activity where compounds 6b and 6g showed significant activity (IC50:0 .4 similar to 2.8 mu g/ml).