Structure-activity relationships of the peptide deformylase inhibitor BB-3497:: Modification of the methylene spacer and the P1′ side chain

被引：32

作者：

Davies, SJ ^{[1
]}

Ayscough, AP ^{[1
]}

Beckett, RP ^{[1
]}

Bragg, RA ^{[1
]}

Clements, JM ^{[1
]}

Doel, S ^{[1
]}

Grew, C ^{[1
]}

Launchbury, SB ^{[1
]}

Perkins, GM ^{[1
]}

Pratt, LM ^{[1
]}

Smith, HK ^{[1
]}

Spavold, ZM ^{[1
]}

Thomas, SW ^{[1
]}

Todd, RS ^{[1
]}

Whittaker, M ^{[1
]}

机构：

[1] British Biotech Pharmaceut Ltd, Oxford OX4 6LY, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2003年 / 13卷 / 16期

关键词：

D O I：

10.1016/S0960-894X(03)00532-8

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Structural modifications to the peptide deformylase inhibitor BB-3497 are described. In this paper, we describe the initial SAR around this lead for modifications to the methylene spacer and the P1' side chain. Enzyme inhibition and antibacterial activity data revealed that the optimum distance between the N-formyl hydroxylamine metal binding group and the P1' side chain is one unsubstituted methylene unit. Additionally, lipophilic P1' side chains that closely mimic the methionine residue in the substrate provided compounds with the best microbiological profile. (C) 2003 Elsevier Ltd. All rights reserved.

引用

页码：2709 / 2713

页数：5

共 18 条

[1] Communication - Structure of peptide deformylase and identification of the substrate binding site [J].

Becker, A ;

Schlichting, I ;

Kabsch, W ;

Schultz, S ;

Wagner, AFV .

JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (19) :11413-11416

[2] Iron center, substrate recognition and mechanism of peptide deformylase [J].

Becker, A ;

Schlichting, I ;

Kabsch, W ;

Groche, D ;

Schultz, S ;

Wagner, AFV .

NATURE STRUCTURAL BIOLOGY, 1998, 5 (12) :1053-1058

[3]

BECKETT RP, 1993, SYNLETT, P137

[4]

BRIT BIOTECH PHARM, Patent No. 9939704

[5] Crystal structure of the Escherichia coli peptide deformylase [J].

Chan, MK ;

Gong, WM ;

Rajagopalan, PTR ;

Hao, B ;

Tsai, CM ;

Pei, DH .

BIOCHEMISTRY, 1997, 36 (45) :13904-13909

[6] Antibiotic activity and characterization of BB-3497, a novel peptide deformylase inhibitor [J].

Clements, JM ;

Beckett, RP ;

Brown, A ;

Catlin, G ;

Lobell, M ;

Palan, S ;

Thomas, W ;

Whittaker, M ;

Wood, S ;

Salama, S ;

Baker, PJ ;

Rodgers, HF ;

Barynin, V ;

Rice, DW ;

Hunter, MG .

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2001, 45 (02) :563-570

[7]

Clements John M., 2002, Current Medicinal Chemistry - Anti-Infective Agents, V1, P239, DOI 10.2174/1568012023354866

[8]

DAVIES SJ, BIOORG MED CHEM LETT

[9] ASYMMETRIC OXYGENATION OF CHIRAL IMIDE ENOLATES - A GENERAL-APPROACH TO THE SYNTHESIS OF ENANTIOMERICALLY PURE ALPHA-HYDROXY CARBOXYLIC-ACID SYNTHONS [J].

EVANS, DA ;

MORRISSEY, MM ;

DOROW, RL .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1985, 107 (14) :4346-4348

[10] ASYMMETRIC ALKYLATION REACTIONS OF CHIRAL IMIDE ENOLATES - A PRACTICAL APPROACH TO THE ENANTIOSELECTIVE SYNTHESIS OF ALPHA-SUBSTITUTED CARBOXYLIC-ACID DERIVATIVES [J].

EVANS, DA ;

ENNIS, MD ;

MATHRE, DJ .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1982, 104 (06) :1737-1739

← 1 2 →