2-β-D-呋喃核糖基恶唑-4-甲酰胺（奥扎胞苷）的合成与抗肿瘤活性

Synthesis and antitumor activity of 2-beta-D-ribofuranosyloxazole-4-carboxamide (oxazofurin).

作者信息

Franchetti P, Cristalli G, Grifantini M, Cappellacci L, Vittori S, Nocentini G

机构信息

Dipartimento di Scienze Chimiche, Università di Camerino, Italy.

出版信息

J Med Chem. 1990 Oct;33(10):2849-52. doi: 10.1021/jm00172a027.

DOI:10.1021/jm00172a027

PMID:2120442

Abstract

Condensation of 3,4,6-tri-O-benzoyl-2,5-anhydro-D-allonyl chloride (4) with ethyl 2-amino-2-cyanoacetate (5) provided 2-[(3',4',6'-tri-O-benzoyl-2',5'-anhydroallonyl)amino]-2-cyanoa cetate (6). Compound 6 was treated with hydrogen chloride gas to give ethyl 5-amino-2-(2',3',5'-tri-O-benzoyl-beta-D- ribofuranosyl)oxazole-4-carboxylate (8). Reductive dediazotization of blocked nucleoside 8 provided ethyl 2-(2',3',5'-tri-O- benzoyl-beta-D-ribofuranosyl)oxazole-4-carboxylate (10), which after deblocking with sodium methoxide and ammonolysis was converted to 2-beta-D-ribofuranosyl-oxazole-4-carboxamide (oxazofurin, 3), an analogue of the antitumor and antiviral C-nucleoside tiazofurin (1). Oxazofurin (3) was found to be cytotoxic toward B16 murine melanoma cells in culture but inactive against murine leukemia P388 and L1210.

摘要

3,4,6-三-O-苯甲酰基-2,5-脱水-D-阿洛糖基氯（4）与2-氨基-2-氰基乙酸乙酯（5）缩合得到2-[(3',4',6'-三-O-苯甲酰基-2',5'-脱水阿洛糖基)氨基]-2-氰基乙酸乙酯（6）。化合物6用氯化氢气体处理得到5-氨基-2-(2',3',5'-三-O-苯甲酰基-β-D-呋喃核糖基)恶唑-4-羧酸乙酯（8）。对封闭的核苷8进行还原脱重氮化反应得到2-(2',3',5'-三-O-苯甲酰基-β-D-呋喃核糖基)恶唑-4-羧酸乙酯（10），用甲醇钠脱保护并进行氨解后转化为2-β-D-呋喃核糖基-恶唑-4-甲酰胺（恶唑呋林，3），它是抗肿瘤和抗病毒的C-核苷噻唑呋林（1）的类似物。发现恶唑呋林（3）对培养中的B16小鼠黑色素瘤细胞具有细胞毒性，但对小鼠白血病P388和L1210无活性。