Structure-Activity Relationships of cyclo(L-Tyrosyl-L-tyrosine) Derivatives Binding to Mycobacterium tuberculosis CYP121: Iodinated Analogues Promote Shift to High-Spin Adduct

被引：23

作者：

Rajput, Sunnia ^{[1
,2
]}

McLean, Kirsty J. ^{[3
]}

Poddar, Harshwardhan ^{[3
]}

Selvam, Irwin R. ^{[3
]}

Nagalingam, Gayathri ^{[4
]}

Triccas, James A. ^{[4
]}

Levy, Colin W. ^{[3
]}

Munro, Andrew W. ^{[3
]}

Hutton, Craig A. ^{[1
,2
]}

机构：

[1] Univ Melbourne, Sch Chem, 30 Flemington Rd, Parkville, Vic 3010, Australia

[2] Univ Melbourne, Bio21 Mol Sci & Biotechnol Inst, 30 Flemington Rd, Parkville, Vic 3010, Australia

[3] Univ Manchester, Sch Chem, Manchester Inst Biotechnol, Ctr Synthet Biol Fine & Specialty Chem SYNBIOCHEM, 131 Princess St, Manchester M1 7DN, Lancs, England

[4] Univ Sydney, Sydney Med Sch, Dept Infect Dis & Immunol, Sydney, NSW 2006, Australia

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2019年 / 62卷 / 21期

基金：

英国生物技术与生命科学研究理事会; 澳大利亚研究理事会;

关键词：

CRYSTAL-STRUCTURE; CYTOCHROME-P450; ENZYMES; PYRAZINE CHEMISTRY; COUPLING REACTION; IDENTIFICATION; HERQULINE; INSIGHTS; FEATURES; P450; DIKETOPIPERAZINES;

D O I：

10.1021/acs.jmedchem.9b01199

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of analogues of cyclo(L-tyrosyl-L-tyrosine), the substrate of the Mycobacterium tuberculosis enzyme CYP121, have been synthesized and analyzed by UV-vis and electron paramagnetic resonance spectroscopy and by X-ray crystallography. The introduction of iodine substituents onto cyclo(L-tyrosyl-L-tyrosine) results in sub-mu M binding affinity for the CYP121 enzyme and a complete shift to the high-spin state of the heme Fe-III. The introduction of halogens that are able to interact with heme groups is thus a feasible approach to the development of next-generation, tight binding inhibitors of the CYP121 enzyme, in the search for novel antitubercular compounds.

引用

页码：9792 / 9805

页数：14

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