Synthesis and structure-activity relationships of o-sulfonamidoarylhydrazides as inhibitors of LL-diaminopimelate aminotransferase (LL-DAP-AT)

被引：5

作者：

Fan, Chenguang ^{[1
]}

Vederas, John C. ^{[1
]}

机构：

[1] Univ Alberta, Dept Chem, Edmonton, AB T6G 2G2, Canada

来源：

ORGANIC & BIOMOLECULAR CHEMISTRY | 2012年 / 10卷 / 30期

基金：

加拿大自然科学与工程研究理事会;

关键词：

LYSINE BIOSYNTHESIS; PEPTIDOGLYCAN STRUCTURE; SUBSTRATE RECOGNITION; ENZYME; CATALYSIS; MECHANISM; INSIGHTS; PATHWAY; PLANTS; TARGET;

D O I：

10.1039/c2ob00040g

中图分类号：

O62 [有机化学];

学科分类号：

070303 ; 081704 ;

摘要：

Recently, LL-diaminopimelate aminotransferase (LL-DAP-AT), a pyridoxal-5'-phosphate (PLP)-dependent enzyme, was reported to catalyze a key step in the biosynthesis of L-lysine in plants and Chlamydia. Previous screening of a 29 201-compound library against LL-DAP-AT identified an o-sulfonamidoarylhydrazide as a reversible inhibitor with IC50 similar to 5 mu M. Structure-activity relationship (SAR) studies based on this lead compound identified key structural features essential for enzyme inhibition and led to slightly improved inhibitors. Preliminary studies on the mode of inhibition of LL-DAP-AT by this class of compounds are also reported.

引用

页码：5815 / 5819

页数：5

共 26 条

[1] Bacterial diaminopimelate metabolism as a target for antibiotic design
Cox, RJ
Sutherland, A
Vederas, JC
[J]. BIOORGANIC & MEDICINAL CHEMISTRY, 2000, 8 (05) : 843 - 871
[2] Synthesis and in vitro enzyme activity of aza, oxa and thia derivatives of bacterial cell wall biosynthesis intermediates
Cox, RJ
Wang, PSH
[J]. JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 1, 2001, (17): : 2022 - 2034
[3] Nucleophilic catalysis of hydrazone formation and transimination: Implications for dynamic covalent chemistry
Dirksen, Anouk
Dirksen, Sjoerd
Hackeng, Tilman M.
Dawson, Philip E.
[J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2006, 128 (49) : 15602 - 15603
[4] Rapid Oxime and Hydrazone Ligations with Aromatic Aldehydes for Biomolecular Labeling
Dirksen, Anouk
Dawson, Philip E.
[J]. BIOCONJUGATE CHEMISTRY, 2008, 19 (12) : 2543 - 2548
[5] Exploration of inhibitors for diaminopimelate aminotransferase
Fan, Chenguang
Clay, Matthew D.
Deyholos, Michael K.
Vederas, John C.
[J]. BIOORGANIC & MEDICINAL CHEMISTRY, 2010, 18 (06) : 2141 - 2151
[6] Inhibitors of bacterial N-succinyl-L,L-diaminopimelic acid desuccinylase (DapE) and demonstration of in vitro antimicrobial activity
Gillner, Danuta
Armoush, Nicola
Holz, Richard C.
Becker, Daniel P.
[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2009, 19 (22) : 6350 - 6352
[7] Methanogens with pseudomurein use diaminopimelate aminotransferase in lysine biosynthesis
Graham, David E.
Huse, Holly K.
[J]. FEBS LETTERS, 2008, 582 (09) : 1369 - 1374
[8] Biochemical and phylogenetic characterization of a novel diaminopimelate biosynthesis pathway in prokaryotes identifies a diverged form of LL-diaminopimelate aminotransferase
Hudson, Andre O.
Gilvarg, Charles
Leustek, Thomas
[J]. JOURNAL OF BACTERIOLOGY, 2008, 190 (09) : 3256 - 3263
[9] An LL-diaminopimelate aminotransferase defines a novel variant of the lysine biosynthesis pathway in plants
Hudson, AO
Singh, BK
Leustek, T
Gilvarg, C
[J]. PLANT PHYSIOLOGY, 2006, 140 (01) : 292 - 301
[10] Inhibition of lysine biosynthesis: an evolving antibiotic strategy
Hutton, Craig A.
Perugini, Matthew A.
Gerrard, Juliet A.
[J]. MOLECULAR BIOSYSTEMS, 2007, 3 (07) : 458 - 465

← 1 2 3 →