A Simple Computational Tool for Accurate, Quantitative Prediction of One–Electron Reduction Potentials of Hypoxia–Activated Tirapazamine Analogues

Authors

  • Hassan RH Elsaidi Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G 1Z2, Canada. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Alexandria, El Sultan Hussein St. Azarita, Alexandria 21521, Egypt.
  • Leonard I Wiebe Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G 1Z2, Canada. Joint appointment to Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta T6G 2E1, Canada.
  • Piyush Kumar Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G 1Z2, Canada.

DOI:

https://doi.org/10.18433/jpps30602

Abstract

The reduction potentials of bioreductively-activated drugs represent an important design parameter to be accommodated in the course of creating lead compounds and improving the efficacy of older generation drugs.  Reduction potentials are traditionally reported as single–electron reduction potentials, E(1), measured against reference electrodes under strictly defined experimental conditions.  More recently, computational chemists have described redox properties in terms of a molecule’s highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO), in electron volts (eV).  The relative accessibility of HOMO/LUMO data through calculation using today’s computer infrastructure and simplified algorithms make the calculated value (LUMO) attractive in comparison to the accepted but rigorous experimental determination of E(1).  This paper describes the correlations of eV (LUMO) to E(1) for three series of bioreductively–activated benzotriazine di-N-oxides (BTDOs), ring-substituted BTDOs, ring-added BTDOs and a selection of aromatic nitro compounds. The current computational approach is a closed–shell calculation with a single optimization.  Gas phase geometry optimization was followed by a single–point DFT (Density Functional Theory) energy calculation in the gas phase or in the presence of polar solvent.  The resulting DFT–derived LUMO energies (eV) calculated for BTDO analogues in gas phase and in presence of polar solvent (water) exhibited very strong linear correlations with high computational efficiency (r2 = 0.9925) and a very high predictive ability (MAD = 7 mV and RMSD = 9 mV) when compared to reported experimentally determined single–electron reduction potentials.

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Author Biographies

Hassan RH Elsaidi, Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G 1Z2, Canada. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Alexandria, El Sultan Hussein St. Azarita, Alexandria 21521, Egypt.

Department of Oncology

Research Associate

Leonard I Wiebe, Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G 1Z2, Canada. Joint appointment to Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta T6G 2E1, Canada.

Department of Oncology

Professor Emeritus

Piyush Kumar, Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G 1Z2, Canada.

Department of Oncology

Clinical Professor

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Published

2020-06-23

How to Cite

Elsaidi, H. R., Wiebe, L. I., & Kumar, P. (2020). A Simple Computational Tool for Accurate, Quantitative Prediction of One–Electron Reduction Potentials of Hypoxia–Activated Tirapazamine Analogues. Journal of Pharmacy & Pharmaceutical Sciences, 23(1), 231-242. https://doi.org/10.18433/jpps30602

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Section

Pharmaceutical Sciences; Original Research Articles