Potential antitumor alpha-methylene-psi-butyrolactone-bearing nucleic acid bases. 2. Synthesis of 5'-methyl-5'-[2-(5-substituted uracil-1-yl)ethyl]-2'-oxo-3'-methylenetetrahydrofurans.
Ten, heretofore unreported, 5'-methyl-5'-[2-(5-substituted uracil-1-yl)ethyl)]-2'-oxo-3'-methylenetetrahydrofurans (H, F, Cl, Br, I, CH(3), CH(3), CH(2)CH(3), CH=CH(2), SePh) (7a-j) were synthesized and evaluated against four cell lines (K-562, FM-3A, P-388 and U-937). For the preparation of alpha-methylene-gamma-butyrolactone-linked to 5-substituted uracils (7a-j), the convenient Reformasky type reaction was employed which involves the treatment of ethyl alpha-(bromomethyl)acrylate and zinc with the respective 1-(5-substituted uracil-1-yl)-3-butanone (6a-j). The 5-substituted uracil ketones (6a-j) were directly obtained by the respective Michael type reaction of vinyl methyl ketone with the K(2)CO(3) (or NaH)-treated 5-substituted uracils (5a-j) in the presence of acetic acid in the DMF solvent. The alpha-methylene-gamma-butyrolactone compounds showing the most significant antitumor activity are7e, 7f, 7h and7j (inhibitory concentration (IC(50)) ranging from 0.69 to 2.9 mug/ml), while7b, 7g and7i have shown moderate to significant activity. The compounds7a, 7c and7d were found to be inactive. The synthetic intermediate compounds6a-j were also screened and found marginal to moderate activity where compounds6b and6g showed significant activity (IC(50):0.4 approximately 2.8 mug/ml).
Kim
J C
JC
Department of Chemistry, College of Natural Science, Pusan National University, 609-735, Pusan, Korea.
Kim
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Park
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Kim
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Kim
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Choi
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Park
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