3-甲酰基-和3-氰基-2,5,6-三氯吲哚核苷衍生物的合成及抗病毒活性

Synthesis and antiviral activity of 3-formyl- and 3-cyano-2,5,6-trichloroindole nucleoside derivatives.

作者信息

Williams John D, Chen Jiong J, Drach John C, Townsend Leroy B

机构信息

Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48019, USA.

出版信息

J Med Chem. 2004 Nov 4;47(23):5766-72. doi: 10.1021/jm040032n.

DOI:10.1021/jm040032n

PMID:15509175

Abstract

A series of trichlorinated indole nucleosides has been synthesized and tested for activity against human cytomegalovirus (HCMV) and herpes simplex virus type-1 (HSV-1) and for cytotoxicity. The previously reported 3-formyl-2,5,6-trichloro-1-(beta-D-ribofuranosyl)indole (FTCRI) and its 3-cyano homologue (CTCRI) were chemically modified at the 3-position. The formation of hydrazones and oximes of FTCRI was accomplished by a dehydrative addition of the appropriate hydrazine or hydroxylamine derivatives, respectively. A carboxamide oxime and imidate were synthesized from CTCRI by the addition of hydroxylamine or methanol, respectively, to the 3-nitrile substituent. Analogues synthesized from FTCRI generally had less antiviral activity than either FTCRI or CTCRI. However, the derivatives of CTCRI were potent and selective inhibitors of HCMV in vitro. The analogue 2,5,6-trichloro-1-(beta-D-ribofuranosyl)indole-3-carboxamide oxime was especially selective (HCMV IC50 = 0.30 microM, CC50 > 100 microM). None of the analogues had significant activity against HSV-1.

摘要

已合成了一系列三氯代吲哚核苷，并对其抗人巨细胞病毒（HCMV）和单纯疱疹病毒1型（HSV-1）的活性以及细胞毒性进行了测试。先前报道的3-甲酰基-2,5,6-三氯-1-（β-D-呋喃核糖基）吲哚（FTCRI）及其3-氰基同系物（CTCRI）在3位进行了化学修饰。FTCRI的腙和肟的形成分别通过适当的肼或羟胺衍生物的脱水加成来实现。羧酰胺肟和亚氨酸酯分别由CTCRI通过向3-腈取代基中加入羟胺或甲醇合成。由FTCRI合成的类似物通常比FTCRI或CTCRI具有更低的抗病毒活性。然而，CTCRI的衍生物在体外是HCMV的强效和选择性抑制剂。类似物2,5,6-三氯-1-（β-D-呋喃核糖基）吲哚-3-羧酰胺肟具有特别的选择性（HCMV IC50 = 0.30 microM，CC50 > 100 microM）。这些类似物均对HSV-1无显著活性。