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Molecular modeling studies and synthesis of novel quinoxaline derivatives with potential anti-cancer activity as inhibitors of methionine synthase

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Abstract

Methionine synthase (MetS) catalyses the transfer of a methyl group from the methyltetrahydrofolate (MTHF) to homocysteine to produce methionine and tetrahydrofolate. MetS is over-expressed in the cytosol of certain breast and prostate tumor cells. In this article, we designed, synthesized, and evaluated the biological activity of a series of substituted quinoxaline derivatives that mimic the MTHF in the structure. The main aim was to develop inhibitors that could inhibit the enzyme reaction by blocking the binding of MTHF. These inhibitors were docked into the MTHF binding domain in such the same way as MTHF in its binding domain. Compound 4-({(6-nitro-quinoxalin-2-yl)methylamino}methyl)benzoic acid showed the lowest free energy of the binding (−152.62 kJ/mol) and showed the lowest IC50 values of 45 ± 9 and 53 ± 9 μM against two types of cancer cell lines PC-3 and MCF-7, respectively.

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Acknowledgments

My gratitude to Andrew Healy (University of Bradford, IPI) for measuring the mass spectra and to Dennis Farewell (University of Bradford, IPI) who had trained me on using NMR.

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Authors and Affiliations

  1. Organic Chemistry Division, School of Pharmacy, Suez Canal University, Ismailia, 41522, Egypt

    Hosam Elshihawy

  2. Centre for Engineering in Medicine and Surgical Services, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Mohamed Hammad

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  1. Hosam Elshihawy
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  2. Mohamed Hammad
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Corresponding author

Correspondence to Hosam Elshihawy.

Appendix: The free energy of binding

Appendix: The free energy of binding

$$ \Updelta E_{\text{Bind}} = \Updelta E_{\text{Complex}} - (\Updelta E_{\text{Receptor}} + \Updelta E_{\text{Ligand}} ) $$
(1)

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Elshihawy, H., Hammad, M. Molecular modeling studies and synthesis of novel quinoxaline derivatives with potential anti-cancer activity as inhibitors of methionine synthase. Med Chem Res 22, 3405–3415 (2013). https://doi.org/10.1007/s00044-012-0307-4

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  • DOI: https://doi.org/10.1007/s00044-012-0307-4

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