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

S Rajput; KJ McLean; H Poddar; IR Selvam; G Nagalingam; JA Triccas; CW Levy; AW Munro; CA Hutton

Journal article

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

S Rajput, KJ McLean, H Poddar, IR Selvam, G Nagalingam, JA Triccas, CW Levy, AW Munro, CA Hutton

Journal of Medicinal Chemistry | AMER CHEMICAL SOC | Published : 2019

DOI: 10.1021/acs.jmedchem.9b01199

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.

University of Melbourne Researchers

Sunnia Rajput Author

Craig Hutton Author

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Grants

Awarded by University of Melbourne

Funding Acknowledgements

This work was supported by the Australian Research Council (DP180101804 and DP140100174), the University of Melbourne (Manchester-Melbourne Research Fund), and the UK Biotechnology and Biological Sciences Research Council (BBSRC grant award number BB/R009961/1). The authors also wish to thank the BBSRC-funded Centre for Synthetic Biology of Fine and Specialty Chemicals (SYNBIO-CHEM, BB/M017702/1) for access to analytical equipment. The authors acknowledge Diamond Light Source for time on beamline i03 under proposals MX8997-25 and MX17773-10 and thank the beamline scientists for their assistance with crystallographic data collection. The authors thank Dr Nick Williamson and the Bio21 MSPF for their assistance with compound purification and characterization.