IRREVERSIBLE ENZYME INHIBITORS .163. ACTIVE-SITE-DIRECTED IRREVERSIBLE INHIBITORS OF CYTOSINE NUCLEOSIDE DEAMINASE DERIVED FROM 1-PHENOXYPROPYL-5-ARYLCYTOSINES

被引：9

作者：

BAKER, BR

KELLEY, JL

机构：

[1] Department of Chemistry, University of California at Santa Barbara

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1969年 / 12卷 / 06期

关键词：

D O I：

10.1021/jm00306a018

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Eighteen candidate irreversible inhibitors of cytosine nucleoside deaminase were synthesized: fifteen (3-17) were bridged to a terminal sulfonyl fluoride group from the phenoxy moiety of 5-(3,-4-dichlorophenyl)-1-phenoxypropyicytosine and three (18-20) from the 5-phenyl moiety of 1-phenoxypropyl-5-phenyleytosine. Of these 18 compounds, 15 showed no irreversible inhibition, one (9) showed poor irreversible inhibition, one (18) showed good irreversible inhibition, and one (3) showed excellent irreversible inhibition. 5-(3,4-Dichlorophenyl)-1-[p-(p-fluorosulfonylbenzamido))pheiioxypropyl]cytosine (3) had a Ki ~ 50μM; at 100μM, 3 gave complete inactivation of the enzyme with a half-life of <2 min: that 3 inactivated the enzyme via a reversible enzyme inhibitor complex, the so-called active-site-directed mechanism, was strongly supported by structure-activity relationships. © 1969, American Chemical Society. All rights reserved.

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页码：1046 / &

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