Potential antitumor alpha-methylene-gamma-butyrolactone-bearing nucleic acid base. 3. Synthesis of 5'-methyl-5'-[(6-substituted-9H-purin-9-yl)methyl]-2'-oxo-3'- methylenetetrahydrofurans.
Search for a new alpha-methylene-gamma-butyrolactone-bearing 6-substituted purine as a potential antitumor agent has led to synthesize seven, hitherto unreported, 5'-Methyl-5'-[(6-substituted-9H-purin-9-yl)methyl]-2'-oxo-3'- methylenetetrahydrofurans (H, Cl, I, CH3, NH2, SH, > C=O) (6a-g). These include 5'-Methyl-5'-[(9H-purin-9-yl)methyl]-2'-oxo-3'-methylenetetrahydrofur ans (6a), 5'-Methyl-5'-[(chloro-9H-purin-9-yl)methyl]-2'-oxo-3'- methylenetetrahydrofurans (6b), 5'-Methyl-5'-[(6-iodo-9H-purin-9-yl) methyl]-2'-oxo-3'-methylenetetrahydrofurans (6c), 5'-Methyl-5'-[(6-methyl-9H-purin-9-yl) methyl]-2'-oxo-3'-methylenetetrahydrofurans (6d), 5'-Methyl-5'-[(9H-adenin-9-yl)methyl]-2'-oxo-3-methylenetetrahy drofurans (6e), 5'-Methyl-5'-[(6-mercapto-9H-purin-9-yl) methyl]-2'-oxo-3'-methylenetetrahydrofurans (6f) and 5'-Methyl-5'-[(9H-hypoxanthin-9-yl)methyl]-2'-oxo-3'- methylenetetrahydrofurans (6g) which were made by the Reformatsky-type reaction of ethyl alpha-(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-yl)-2-propanone (5c), 1-(6-methyl-9H-purin-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-9-yl)-2-propanone (5g) were directly obtained by the alkylation of the 6-substituted purine bases with the chloroacetone in the presence of K2CO3 (or NaH) under DMF (or DMSO). The preliminary in vitro cytotoxicity assay for the synthetic alpha-methylene-gamma-butyro-lactone compounds (6a-g) were determined against three cell lines (PM-3A, P-388, and K-562) and showed the moderate antitumor activity (IC50 ranged from 1.4 to 4.3 micrograms/ml) with the compound 5'-methyl-5'-[(9H-hypoxanthin-9-yl)methyl]-2'-oxo-3'- methylenetetrahydrofuran (6g) showing the least antitumor activity.
Kim
J C
JC
Department of Chemistry, College of Natural Science, Pusan National University, Korea.
Kim
S H
SH
Kim
J A
JA
Choi
S K
SK
Park
W W
WW
D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D011687:Purines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D011687:Purines; D015107:4-Butyrolactone