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Suppression of PGE2 production via disruption of MAPK phosphorylation by unsymmetrical dicarbonyl curcumin derivatives

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Abstract

Curcumin is an important molecule found in turmeric plants and has been reported to exhibit some profound anti-inflammatory activities by interacting with several important molecular targets found in the mitogen-activated protein kinase and NF-κβ pathways. As part of our continuing effort to search for new anti-inflammatory agents with better in vitro and in vivo efficacies, we have synthesized a series of new unsymmetrical dicarbonyl curcumin derivatives and tested their effects on prostaglandin E2 secretion level in interferon-γ/lipopolysaccharide-activated macrophage cells. Among those, five compounds exhibited remarkable suppression on prostaglandin E2 production with IC50 values ranging from 0.87 to 18.41 µM. The most potent compound 17f was found to down-regulate the expression of cyclooxygenase-2 mRNA suggesting that this series of compounds could possibly target the mitogen-activated protein kinase signal transduction pathway. Whilst the compound did not affect the expression of the conventional mitogen-activated protein kinases, the results suggest that it could disrupt the phosphorylation and activation of the proteins particularly the c-Jun N-terminal kinases. Finally, the binding interactions were examined using the molecular docking and dynamics simulation approaches.

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Acknowledgements

This work was financially supported by ScienceFund (02-01-02-SF00665), Ministry of Science, Technology & Innovation, Malaysia and FRGS (FRGS/2/2014/ST01/UKM/02/3), Ministry of High Education, Malaysia. Authors also thank Universiti Kebangsaan Malaysia for the funds provided under the Research University Grant UKM-DIP-2014-16.

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Authors and Affiliations

  1. Drug and Herbal Research Centre, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, Kuala Lumpur, 50300, Malaysia

    Mohd Fadhlizil Fasihi Mohd Aluwi, Kamal Rullah, Md. Areeful Haque, Waqas Ahmad, Muhammad Wahab Amjad, Nurul Amira Fahmizar, Juriyati Jalil, Ibrahim Jantan & Kok Wai Lam

  2. Nanotechnology and Catalyst Research Centre (NANOCAT), Block A, Level 3, Institute of Postgraduate Studies, Universiti of Malaya, Kuala Lumpur, 50603, Indonesia

    Mohd Fadhlizil Fasihi Mohd Aluwi & Kamal Rullah

  3. Sekolah Tinggi Ilmu Farmasi Riau, Universitas Riau, Kampus Bina Widya, Km 12.5, Simpang Baru-Pekanbaru, 28293, Indonesia

    Kamal Rullah

  4. School of Chemical Sciences and Food Technology, Universiti Kebangsaan Malaysia, Bangi, Selangor, 43600, Malaysia

    Bohari M. Yamin

  5. Laboratory of Natural Product, Institute of Bioscience, Universiti Putra Malaysia, Serdang, Selangor, 43400, Malaysia

    Sze Wei Leong & Faridah Abas

  6. Atta-Ur- Rahman Institute for Natural Product Discovery, Universiti Teknologi MARA Kampus Puncak Alam,, 42300, Puncak Alam, Selangor, Malaysia

    Nor Hadiani Ismail

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  1. Mohd Fadhlizil Fasihi Mohd Aluwi
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  2. Kamal Rullah
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  7. Sze Wei Leong
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  8. Nurul Amira Fahmizar
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  9. Juriyati Jalil
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  10. Faridah Abas
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  11. Nor Hadiani Ismail
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  12. Ibrahim Jantan
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  13. Kok Wai Lam
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Correspondence to Kok Wai Lam.

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Mohd Aluwi, M.F.F., Rullah, K., Haque, M.A. et al. Suppression of PGE2 production via disruption of MAPK phosphorylation by unsymmetrical dicarbonyl curcumin derivatives. Med Chem Res 26, 3323–3335 (2017). https://doi.org/10.1007/s00044-017-2025-4

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  • DOI: https://doi.org/10.1007/s00044-017-2025-4

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