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KMID : 0043319980210040458
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Archives of Pharmacal Research
1998 Volume.21 No. 4 p.458 ~ p.464
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Potential Antitumor α-Methylene-r-butyrolactone-Bearing Nucleic Acid Base. 3. Synthesis of 5[1]-Methyl-5[1]-[(6-substituted-9H-purin-9-yl)methyl]-2[1]-oxo-3[1]-methylenetetrahydrofurans
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Kim Jack-C.
Kim Si-Hwan
Kim Ji-A
Choi Soon-Kyu
Park Won-Woo
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Abstract
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Search for a new -methylene--butyrolactone-bearing 6-substituted purine as a potental antitumor agent has led to synthesize seven, hitherto unreported, -Methyl--[(6-substituted-9H-purin-9-yl)methyl]--oxo-- methylenetetrahydrofurans (H, Cl, l, , , SH, >C=O) (6a-g). These include -Methyl--[(9H-purin-9-yl)methyll--oxo- -methylenetetrahydrofurans (6a), -Methyl--[(6-chloro-9H-purin-9-yl)methyl]--oxo--methylenetetrahydr ofurans (6b), -Methyl--[(6-chloro-9H-purin-9-yl) methyl]--oxo--methylenetetrahydrofurans (6c), -Methyl--[(6-methyl-9H-purin-9-yl) methyl]--oxo--methylenetetrahydrofurans (6d), -Methyl--[(9H-adenin-9-yl)methyll--oxo--methylenetetrahydrofurans (6e), -Methyl--[(6-mercapto-9H-purin-9-yl) methyl]--oxo--methylenetetrahydrofurans (6f) and -Methyl--[(9H-hypoxanthin-9-yl)methyll--oxo--methylenetetrahydrof urans (6g) which were made by the Reformatsky-type reaction of ethyl -(bromomethyl) acrylate with the corresponding (6-substituted-9H-purin-9-yl)-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-propanone (5b), 1-(6-iodo-9H-purin-9-yi)-2-propanone (5c), 1-(6-methyl-9H-purin-9-yl)-2-propanone (5d), 1-(9H-adenin-9-yl)-2-propanone (Se), 1-(6-mercapto-9H-purin-9-yl)-2-propanone (5f), and 1-(9H-hypoxanthin-9-yl)-2-propanone (5g) were directly obtained by the alkylation of the 6-substituted purine bases with the chloroacetone in the presence of (or NaH) under DMF (or DMSO). The preliminary in vitro cytotoxcity assay for the synthetic .alpha.-methylene-y-butyro-lactone compounds (6a-g) were determined against three cell lines (PM-3A, P-388, and K-562) and showed the moderate antitumor activity ( ranged from 1.4 to 4.3 /ml) with the compound -methyl- -[(9H-hypoxanthin-9-yl)methyl]--oxo--methylenetetrahydrofuran (6g) showing the least antitumor activity.
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KEYWORD
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5[1]-Methyl-5[1]-[(6-substituted-9H-purin-9-yl)methyl]2[1]-oxo-3[1]-methylenetetrahydrofuran, 6-Substituted-9H-purin-9-yl-2-propanone, Cytotoxic moiety, Antitumor activity, IC, Reformatsky reaction, Human chronic myelogenous (K-562), Mouse lymphoid neoplasma (P-388), Mouse mammary carcinoma (FM-3A)
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