POTENTIAL ANTITUMOR ALPHA-METHYLENE-GAMMA-BUTYROLACTONE-BEARING NUCLEIC-ACID BASE - 3 - SYNTHESIS OF N-9-YL)METHYL]-2'-OXO-3'-METHYLENETETRAHYDROFURANS

Search for a new alpha-methylene-gamma-butyrolactone-bearing 6-substit uted purine as a potental antitumor agent has led to synthesize seven, hitherto unreported, n-9-yl)methyl]-2'-oxo-3'-methylenetetrahydrofura ns (H, CI, I, CH3, NH2, SH, greater-than C=O) (6a-g). These include n- 9-yl)methyl]-2'-oxo-3'-methylenetetrahydrofurans (6a), n-9-yl)methyl]- 2'-oxo-3'-methylenetetrahydrofurans (6a), n-9-yl)methyl]-2'-oxo-3'-met hylenetetrahydrofurans (6c), n-9-yl)methyl]-2'-oxo-3'-methylenetetrahy drofurans (6d), 5'-methyl-5'-[(9H-adenin-9-yl)methyl]-2 '-oxo-3 '-meth ylenetetrahydrofurans (6e), n-9-yl)methyl]-2'-oxo-3'-methylenetetrahyd rofurans (6f) and n-9-yl)methyl]-2'-oxo-3'-methylenetetrahydrofurans ( 6g) which were made by the Reformatsky-type reaction of ethyl alpha-(b romomethyl)acrylate with the corresponding (6-substituted-9H-purin-9-y l)-2-propanone intermediates (5a-g). These ketone intermediates 5a-g, 1-(9H-purin-9-yl)-2-propanone (5a), 1-(6-chloro-9H-purin-9-yl)-2-propa none (5b), 1-(6-iodo-9H-purin-9-yl)-2-propanone (5c), 1-(6-methyl-9H-p urin-9-yl)-2-propanone (5d), 1-(9H-adenin-9-yl)-2-propanone (5e), 1-(6 -mercapto-9H-purin-9-yl)-2-propanone (5f), and 1-(9H-hypoxanthin-3-yl) -2-propanone (5g) were directly obtained by the alkylation of the 6-su bstituted purine bases with the chloroacetone in the presence of K2CO3 , (or NaH) under DMF (or DMSO). The preliminary in vitro cytotoxcity a ssay for the synthetic alpha-methylene-gamma-butyro-lactone compounds (6a-g) were determined against three cell lines (PM-3A, P-388, and K-5 62) and showed the moderate antitumor activity (ICS, ranged from 1.4 t o 4.3 mu g/ml) with the compound in-9-yl)methyl]-2'-oxo-3'-methylenete trahydrofuran (6g) showing the least antitumor activity.