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Synthesis and in vitro evaluation of ferutinol aryl esters for estrogenic activity and affinity toward cannabinoid receptors

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Abstract

Ferutinin (1), the major constituent of Ferula hermonis and other Ferula species, is a sesquiterpene ester with remarkable estrogenic activity, beside other valuable medicinal properties. To investigate the influence of chemical modification of the ferutinin structure on its estrogenic effect and binding affinity toward the cannabinoid CB1 and CB2 receptors, twelve derivatives of 1 were prepared and evaluated in vitro, together with the parent compound, for the respective bioactivities, based on the recent evidence for estrogen–endocannabinoid interaction. Nine of the prepared derivatives (3–11) are new semisynthetic esters of 1. The parent compound ferutinin (1) exhibited the highest level of estrogenic activity (EC50 0.3 μM and a percent maximal 17β-estradiol response of 90 % at 1 µM). Compound 6 was found to be a selective agonist for CB2 receptor (EC50 0.051 μM, Ki 0.025 μM), with much less affinity for CB1 receptor (EC50 97 μM, Ki 48.5 μM). Compound 8 was a selective agonist for CB1 (EC50 62, Ki 0.031 μM) with no affinity toward CB2.

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Acknowledgments

The authors thank the United States Department of Agriculture, Agriculture Research Service Specific Cooperative Agreement No. 58-6408-7-012, for partial support of this work. The authors are also grateful to Dr. Bharathi Avula for helping with the HRESIFTMS analyses.

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Authors and Affiliations

  1. National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, University, MS, 38677, USA

    Ahmed M. Galal Osman

  2. Department of Pharmaceutical Sciences, Chicago State University, Chicago, IL, 60628, USA

    Ehab A. Abourashed

  3. MRI Global, 425 Volker Boulevard, Kansas City, MO, USA

    Desmond Slade

  4. Department of Pharmacognosy, Faculty of Pharmacy, Suez Canal University, Ismailia, 41522, Egypt

    Safwat A. Ahmed

  5. ElSohly Laboratories, Inc., 5 Industrial Park Drive, Oxford, MS, 38655, USA

    Waseem Gul & Mahmoud A. ElSohly

  6. National Center for Natural Products Research and Department of Biomolecular Science, School of Pharmacy, The University of Mississippi, University, MS, 38677, USA

    Shabana I. Khan

  7. Department of Pharmaceutical Chemistry, Asuit University, Asuit, Egypt

    Tarek Abo Elfadl

  8. National Center for Natural Products Research, The University of Mississippi, University, MS, 38677, USA

    Olivia R. Dale

  9. Division of Medicinal Chemistry, Department of Biomolecular Science, University of Mississippi, University, MS, 38677, USA

    Afeef S. Husni & Stephen J. Cutler

  10. Department of Pharmaceutics, University of Mississippi, University, MS, 38677, USA

    Mahmoud A. ElSohly

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  1. Ahmed M. Galal Osman
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  2. Ehab A. Abourashed
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  3. Desmond Slade
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  4. Safwat A. Ahmed
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  5. Waseem Gul
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  7. Tarek Abo Elfadl
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  8. Olivia R. Dale
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  9. Afeef S. Husni
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  10. Stephen J. Cutler
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  11. Mahmoud A. ElSohly
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Corresponding authors

Correspondence to Ahmed M. Galal Osman or Mahmoud A. ElSohly.

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Osman, A.M.G., Abourashed, E.A., Slade, D. et al. Synthesis and in vitro evaluation of ferutinol aryl esters for estrogenic activity and affinity toward cannabinoid receptors. Med Chem Res 24, 2670–2678 (2015). https://doi.org/10.1007/s00044-015-1319-7

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  • DOI: https://doi.org/10.1007/s00044-015-1319-7

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