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Medicinal Chemistry Research

, Volume 26, Issue 12, pp 3323–3335 | Cite as

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

  • Mohd Fadhlizil Fasihi Mohd Aluwi
  • Kamal Rullah
  • Md. Areeful Haque
  • Bohari M. Yamin
  • Waqas Ahmad
  • Muhammad Wahab Amjad
  • Sze Wei Leong
  • Nurul Amira Fahmizar
  • Juriyati Jalil
  • Faridah Abas
  • Nor Hadiani Ismail
  • Ibrahim Jantan
  • Kok Wai Lam
Original Research
  • 148 Downloads

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.

Keywords

Prostaglandin E2 COX-2 mRNA expression MAPK phosphorylation Molecular Dynamic simulation Unsymmetrical dicarbonyl curcumin derivatives 

Notes

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.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

44_2017_2025_MOESM1_ESM.doc (3.4 mb)
Supplementary Data

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Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Mohd Fadhlizil Fasihi Mohd Aluwi
    • 1
    • 2
  • Kamal Rullah
    • 1
    • 2
    • 3
  • Md. Areeful Haque
    • 1
  • Bohari M. Yamin
    • 4
  • Waqas Ahmad
    • 1
  • Muhammad Wahab Amjad
    • 1
  • Sze Wei Leong
    • 5
  • Nurul Amira Fahmizar
    • 1
  • Juriyati Jalil
    • 1
  • Faridah Abas
    • 5
  • Nor Hadiani Ismail
    • 6
  • Ibrahim Jantan
    • 1
  • Kok Wai Lam
    • 1
  1. 1.Drug and Herbal Research Centre, Faculty of PharmacyUniversiti Kebangsaan MalaysiaKuala LumpurMalaysia
  2. 2.Nanotechnology and Catalyst Research Centre (NANOCAT), Block A, Level 3, Institute of Postgraduate StudiesUniversiti of MalayaKuala LumpurIndonesia
  3. 3.Sekolah Tinggi Ilmu Farmasi RiauUniversitas RiauSimpang Baru-PekanbaruIndonesia
  4. 4.School of Chemical Sciences and Food TechnologyUniversiti Kebangsaan MalaysiaBangiMalaysia
  5. 5.Laboratory of Natural Product, Institute of BioscienceUniversiti Putra MalaysiaSerdangMalaysia
  6. 6.Atta-Ur- Rahman Institute for Natural Product DiscoveryUniversiti Teknologi MARA Kampus Puncak Alam,Puncak AlamMalaysia

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