潜在的含α-亚甲基-γ-丁内酯的抗肿瘤核酸碱基。3. 5'-甲基-5'-[(6-取代-9H-嘌呤-9-基)甲基]-2'-氧代-3'-亚甲基四氢呋喃的合成。

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.

作者信息

Kim J C, Kim S H, Kim J A, Choi S K, Park W W

机构信息

Department of Chemistry, College of Natural Science, Pusan National University, Korea.

出版信息

Arch Pharm Res. 1998 Aug;21(4):458-64. doi: 10.1007/BF02974643.

DOI:10.1007/BF02974643

PMID:9875476

Abstract

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.

摘要

寻找一种新型的带有α-亚甲基-γ-丁内酯的6-取代嘌呤作为潜在的抗肿瘤药物，已促使人们合成了七种迄今未报道的5'-甲基-5'-[(6-取代-9H-嘌呤-9-基)甲基]-2'-氧代-3'-亚甲基四氢呋喃（H、Cl、I、CH3、NH2、SH、>C=O）（6a - g）。这些化合物包括5'-甲基-5'-[(9H-嘌呤-9-基)甲基]-2'-氧代-3'-亚甲基四氢呋喃（6a）、5'-甲基-5'-[(氯-9H-嘌呤-9-基)甲基]-2'-氧代-3'-亚甲基四氢呋喃（6b）、5'-甲基-5'-[(6-碘-9H-嘌呤-9-基)甲基]-2'-氧代-3'-亚甲基四氢呋喃（6c）、5'-甲基-5'-[(6-甲基-9H-嘌呤-9-基)甲基]-2'-氧代-3'-亚甲基四氢呋喃（6d）、5'-甲基-5'-[(9H-腺嘌呤-9-基)甲基]-2'-氧代-3-亚甲基四氢呋喃（6e）、5'-甲基-5'-[(6-巯基-9H-嘌呤-9-基)甲基]-2'-氧代-3'-亚甲基四氢呋喃（6f）和5'-甲基-5'-[(9H-次黄嘌呤-9-基)甲基]-2'-氧代-3'-亚甲基四氢呋喃（6g），它们是通过α-(溴甲基)丙烯酸乙酯与相应的（6-取代-9H-嘌呤-9-基）-2-丙酮中间体（5a - g）进行Reformatsky型反应制得的。这些酮中间体5a - g，即1-(9H-嘌呤-9-基)-2-丙酮（5a）、1-(6-氯-9H-嘌呤-9-基)-2-丙酮（5b）、1-(6-碘-9H-嘌呤-9-基)-2-丙酮（5c）、1-(6-甲基-9H-嘌呤-9-基)-2-丙酮（5d）、1-(9H-腺嘌呤-9-基)-2-丙酮（5e）、1-(6-巯基-9H-嘌呤-9-基)-2-丙酮（5f）和1-(9H-次黄嘌呤-9-基)-2-丙酮（5g），是通过在K2CO3（或NaH）存在下，于DMF（或DMSO）中用氯丙酮对6-取代嘌呤碱进行烷基化反应直接得到的。对合成的α-亚甲基-γ-丁内酯化合物（6a - g）针对三种细胞系（PM - 3A、P - 388和K - 562）进行的初步体外细胞毒性试验表明，它们具有中等抗肿瘤活性（IC50范围为1.4至4.3微克/毫升），其中化合物5'-甲基-5'-[(9H-次黄嘌呤-9-基)甲基]-2'-氧代-3'-亚甲基四氢呋喃（6g）的抗肿瘤活性最低。