Structure-activity relationships of the peptide deformylase inhibitor BB-3497:: Modification of the P2′ and P3′ side chains

被引：24

作者：

Davies, SJ ^{[1
]}

Ayscough, AP ^{[1
]}

Beckett, RP ^{[1
]}

Clements, JM ^{[1
]}

Doel, S ^{[1
]}

Pratt, LM ^{[1
]}

Spavold, ZM ^{[1
]}

Thomas, SW ^{[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)00533-X

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 both the P2' and P3' side chains. Enzyme inhibition and antibacterial activity data revealed that a variety of substituents are tolerated at the P2' and P3' positions of the inhibitor backbone. The data from this study highlights the potential for modification at the P2' and P3' positions to optimise the physicochemical properties. (C) 2003 Elsevier Ltd. All rights reserved.

引用

页码：2715 / 2718

页数：4

共 14 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] 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

[4] 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

[5]

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

[6]

DAVIES SJ, BIOORG MED CHEM LETT

[7]

Giglione C, 2001, Expert Opin Ther Targets, V5, P41, DOI 10.1517/14728222.5.1.41

[8] The crystal structures of four peptide deformylases bound to the antibiotic actinonin reveal two distinct types: A platform for the structure-based design of antibacterial agents [J].

Guilloteau, JP ;

Mathieu, M ;

Giglione, C ;

Blanc, V ;

Dupuy, A ;

Chevrier, M ;

Gil, P ;

Famechon, A ;

Meinnel, T ;

Mikol, V .

JOURNAL OF MOLECULAR BIOLOGY, 2002, 320 (05) :951-962

[9] DEFORMYLATION AND PROTEIN BIOSYNTHESIS [J].

LIVINGSTON, DM ;

LEDER, P .

BIOCHEMISTRY, 1969, 8 (01) :435-+

[10] Design and synthesis of substrate analogue inhibitors of peptide deformylase [J].

Meinnel, T ;

Patiny, L ;

Ragusa, S ;

Blanquet, S .

BIOCHEMISTRY, 1999, 38 (14) :4287-4295

← 1 2 →