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Isosteres of hydroxypyridinethione as drug-like pharmacophores for metalloenzyme inhibition

  • Rebecca N. Adamek
  • Cy V. Credille
  • Benjamin L. Dick
  • Seth M. Cohen
Original Paper
Part of the following topical collections:
  1. Alison Butler: Papers in Celebration of Her 2018 ACS Alfred Bader Award in Bioorganic or Bioinorganic Chemistry

Abstract

Hydroxypyridinethiones (HOPTOs) are strong ligands for metal ions and potentially useful pharmacophores for inhibiting metalloenzymes relevant to human disease. However, HOPTOs have been sparingly used in drug discovery efforts due, in part, to concerns that this scaffold will act as a promiscuous, non-selective metalloenzyme inhibitor, as well as possess poor pharmacokinetics (PK), which may undermine drug candidates containing this functional group. To advance HOPTOs as a useful pharmacophore for metalloenzyme inhibitors, a library of 22 HOPTO isostere compounds has been synthesized and investigated. This library demonstrates that it is possible to maintain the core metal-binding pharmacophore (MBP) while generating diversity in structure, electronics, and PK properties. This HOPTO library has been screened against a set of four different metalloenzymes, demonstrating that while the same metal-binding donor atoms are maintained, there is a wide range of activity between metalloenzyme targets. Overall, this work shows that HOPTO isosteres are useful MBPs and valuable scaffolds for metalloenzyme inhibitors.

Keywords

Fragment-based drug discovery Hydroxypyridinethione Inhibitor Isostere Metal-binding pharmacophore Metalloenzyme 

Abbreviations

HOPO

Hydroxypyridine

HOPTO

Hydroxypyridinethione

MBI

Metal-binding isostere

MBP

Metal-binding pharmacophore

PK

Pharmacokinetic

Notes

Acknowledgements

This work was supported by the National Institutes of General Medical Sciences (R01-GM111926). R.N.A. was supported by the National Institute of Health Chemical Biology Interfaces Training Grant UC San Diego (T32GM112584-01). We thank Prof. Arnold Rheingold and Dr. Curtis Moore (U.C. San Diego) for assistance with crystallographic data collection and structure determination. We also thank Dr. Yongxuan Su (U.C. San Diego) for mass spectrometry sample analysis at The Molecular Mass Spectrometry Facility. We thank Dr. Carlo Ballatore for aiding with Sirius PK analysis. We thank Dr. Yuyong Ma for preparing compound 11. S.M.C. is a co-founder, has an equity interest, and receives income as member of the Scientific Advisory Board for Cleave Biosciences and is a co-founder, has an equity interest, and a member of the Scientific Advisory Board for Forge Therapeutics. Both companies may potentially benefit from the research results of certain projects in the laboratory of S.M.C. The terms of this arrangement have been reviewed and approved by the University of California, San Diego, in accordance with its conflict of interest policies.

Supplementary material

775_2018_1593_MOESM1_ESM.pdf (1.1 mb)
Supplementary material 1 (PDF 1129 kb)

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Copyright information

© SBIC 2018

Authors and Affiliations

  • Rebecca N. Adamek
    • 1
  • Cy V. Credille
    • 1
  • Benjamin L. Dick
    • 1
  • Seth M. Cohen
    • 1
  1. 1.Department of Chemistry and BiochemistryUniversity of CaliforniaSan DiegoUSA

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