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

Sunnia Rajput; Kirsty J. McLean; Harshwardhan Poddar; Irwin R. Selvam; Gayathri Nagalingam; James A. Triccas; Colin W. Levy; Andrew W. Munro; Craig A. Hutton

doi:10.1021/acs.jmedchem.9b01199

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

Sunnia Rajput, Kirsty J. McLean, Harshwardhan Poddar, Irwin R. Selvam, Gayathri Nagalingam, James A. Triccas, Colin W. Levy, Andrew W. Munro, Craig A. Hutton

Research output: Contribution to journal › Article › peer-review

24 Citations (Scopus)

Abstract

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-μM 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.

Original language	English
Pages (from-to)	9792-9805
Number of pages	14
Journal	Journal of Medicinal Chemistry
Volume	62
Issue number	21
Early online date	16 Oct 2019
DOIs	https://doi.org/10.1021/acs.jmedchem.9b01199
Publication status	Published - 14 Nov 2019
Externally published	Yes

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SDG 3 Good Health and Well-being

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Rajput, S., McLean, K. J., Poddar, H., Selvam, I. R., Nagalingam, G., Triccas, J. A., Levy, C. W., Munro, A. W., & Hutton, C. A. (2019). Structure-Activity Relationships of cyclo(l -Tyrosyl- l -tyrosine) Derivatives Binding to Mycobacterium tuberculosis CYP121: Iodinated Analogues Promote Shift to High-Spin Adduct. Journal of Medicinal Chemistry, 62(21), 9792-9805. https://doi.org/10.1021/acs.jmedchem.9b01199

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

abstract = "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-μM binding affinity for the CYP121 enzyme and a complete shift to the high-spin state of the heme FeIII. 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.",

keywords = "Cytochrome P-450 Enzyme System, Dipeptides, Halogenation, Models, Molecular, Mycobacterium tuberculosis, Protein binding, Protein Conformation, Structure-Activity Relationship",

author = "Sunnia Rajput and McLean, \{Kirsty J.\} and Harshwardhan Poddar and Selvam, \{Irwin R.\} and Gayathri Nagalingam and Triccas, \{James A.\} and Levy, \{Colin W.\} and Munro, \{Andrew W.\} and Hutton, \{Craig A.\}",

year = "2019",

month = nov,

day = "14",

doi = "10.1021/acs.jmedchem.9b01199",

language = "English",

volume = "62",

pages = "9792--9805",

journal = "Journal of Medicinal Chemistry",

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Rajput, S, McLean, KJ, Poddar, H, Selvam, IR, Nagalingam, G, Triccas, JA, Levy, CW, Munro, AW & Hutton, CA 2019, 'Structure-Activity Relationships of cyclo(l -Tyrosyl- l -tyrosine) Derivatives Binding to Mycobacterium tuberculosis CYP121: Iodinated Analogues Promote Shift to High-Spin Adduct', Journal of Medicinal Chemistry, vol. 62, no. 21, pp. 9792-9805. https://doi.org/10.1021/acs.jmedchem.9b01199

Structure-Activity Relationships of cyclo(l -Tyrosyl- l -tyrosine) Derivatives Binding to Mycobacterium tuberculosis CYP121: Iodinated Analogues Promote Shift to High-Spin Adduct. / Rajput, Sunnia; McLean, Kirsty J.; Poddar, Harshwardhan et al.
In: Journal of Medicinal Chemistry, Vol. 62, No. 21, 14.11.2019, p. 9792-9805.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Structure-Activity Relationships of cyclo(l -Tyrosyl- l -tyrosine) Derivatives Binding to Mycobacterium tuberculosis CYP121

T2 - Iodinated Analogues Promote Shift to High-Spin Adduct

AU - Rajput, Sunnia

AU - McLean, Kirsty J.

AU - Poddar, Harshwardhan

AU - Selvam, Irwin R.

AU - Nagalingam, Gayathri

AU - Triccas, James A.

AU - Levy, Colin W.

AU - Munro, Andrew W.

AU - Hutton, Craig A.

PY - 2019/11/14

Y1 - 2019/11/14

N2 - 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-μM binding affinity for the CYP121 enzyme and a complete shift to the high-spin state of the heme FeIII. 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.

AB - 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-μM binding affinity for the CYP121 enzyme and a complete shift to the high-spin state of the heme FeIII. 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.

KW - Cytochrome P-450 Enzyme System

KW - Dipeptides

KW - Halogenation

KW - Models, Molecular

KW - Mycobacterium tuberculosis

KW - Protein binding

KW - Protein Conformation

KW - Structure-Activity Relationship

UR - https://www.scopus.com/pages/publications/85074617545

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DO - 10.1021/acs.jmedchem.9b01199

M3 - Article

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AN - SCOPUS:85074617545

SN - 0022-2623

VL - 62

SP - 9792

EP - 9805

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 21

ER -

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

Abstract

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