Synthesis of unsymmetrical monocarbonyl curcumin analogues with potent inhibition on prostaglandin E2 production in LPS-induced murine and human macrophages cell lines

Mohd Fadhlizil Fasihi Mohd Aluwi, Kamal Rullah, Bohari Mohd. Yamin, Sze Wei Leong, Mohd Nazri Abdul Bahari, Sock Jin Lim, Siti Munirah Mohd Faudzi, Juriyati Jalil, Faridah Abas, Norsyahida Mohd Fauzi, Nor Hadiani Ismail, Ibrahim Jantan, Kok Wai Lam

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

The syntheses and bioactivities of symmetrical curcumin and its analogues have been the subject of interest by many medicinal chemists and pharmacologists over the years. To improve our understanding, we have synthesized a series of unsymmetrical monocarbonyl curcumin analogues and evaluated their effects on prostaglandin E2 production in lipopolysaccharide-induced RAW264.7 and U937 cells. Initially, compounds 8b and 8c exhibited strong inhibition on the production of PGE2 in both LPS-stimulated RAW264.7 (8b, IC50 = 12.01 M and 8c, IC50 = 4.86 μM) and U937 (8b, IC50 = 3.44 μM and 8c, IC50 = 1.65 μM) cells. Placing vanillin at position Ar2 further improved the potency when both compounds 15a and 15b significantly lowered the PGE2 secretion level (RAW264.7: 15a, IC50 = 0.78 μM and 15b, IC50 = 1.9 μM while U937: 15a, IC50 = 0.95 μM and 15b, IC50 = 0.92 μM). Further experiment showed that compounds 8b, 8c, 15a and 15b did not target the activity of downstream inflammatory COX-2 mediator. Finally, docking simulation on protein targets COX-2, IKK-β, ERK, JNK2, p38α and p38β were performed using the conformation of 15a determined by single-crystal XRD.

Original languageEnglish
Pages (from-to)2531-2538
Number of pages8
JournalBioorganic and Medicinal Chemistry Letters
Volume26
Issue number10
DOIs
Publication statusPublished - 1 May 2016

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Curcumin
Macrophages
Dinoprostone
Inhibitory Concentration 50
Cells
Cell Line
Bioactivity
Lipopolysaccharides
Conformations
Single crystals
U937 Cells
Proteins
Experiments

Keywords

  • Cyclooxygenase-2
  • Prostaglandin E
  • RAW264.7
  • Single-crystal XRD
  • U937
  • Unsymmetrical curcumin analogues

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Molecular Biology
  • Molecular Medicine
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

Cite this

Synthesis of unsymmetrical monocarbonyl curcumin analogues with potent inhibition on prostaglandin E2 production in LPS-induced murine and human macrophages cell lines. / Mohd Aluwi, Mohd Fadhlizil Fasihi; Rullah, Kamal; Mohd. Yamin, Bohari; Leong, Sze Wei; Abdul Bahari, Mohd Nazri; Lim, Sock Jin; Mohd Faudzi, Siti Munirah; Jalil, Juriyati; Abas, Faridah; Mohd Fauzi, Norsyahida; Ismail, Nor Hadiani; Jantan, Ibrahim; Lam, Kok Wai.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 26, No. 10, 01.05.2016, p. 2531-2538.

Research output: Contribution to journalArticle

Mohd Aluwi, Mohd Fadhlizil Fasihi ; Rullah, Kamal ; Mohd. Yamin, Bohari ; Leong, Sze Wei ; Abdul Bahari, Mohd Nazri ; Lim, Sock Jin ; Mohd Faudzi, Siti Munirah ; Jalil, Juriyati ; Abas, Faridah ; Mohd Fauzi, Norsyahida ; Ismail, Nor Hadiani ; Jantan, Ibrahim ; Lam, Kok Wai. / Synthesis of unsymmetrical monocarbonyl curcumin analogues with potent inhibition on prostaglandin E2 production in LPS-induced murine and human macrophages cell lines. In: Bioorganic and Medicinal Chemistry Letters. 2016 ; Vol. 26, No. 10. pp. 2531-2538.
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AU - Mohd Aluwi, Mohd Fadhlizil Fasihi

AU - Rullah, Kamal

AU - Mohd. Yamin, Bohari

AU - Leong, Sze Wei

AU - Abdul Bahari, Mohd Nazri

AU - Lim, Sock Jin

AU - Mohd Faudzi, Siti Munirah

AU - Jalil, Juriyati

AU - Abas, Faridah

AU - Mohd Fauzi, Norsyahida

AU - Ismail, Nor Hadiani

AU - Jantan, Ibrahim

AU - Lam, Kok Wai

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AB - The syntheses and bioactivities of symmetrical curcumin and its analogues have been the subject of interest by many medicinal chemists and pharmacologists over the years. To improve our understanding, we have synthesized a series of unsymmetrical monocarbonyl curcumin analogues and evaluated their effects on prostaglandin E2 production in lipopolysaccharide-induced RAW264.7 and U937 cells. Initially, compounds 8b and 8c exhibited strong inhibition on the production of PGE2 in both LPS-stimulated RAW264.7 (8b, IC50 = 12.01 M and 8c, IC50 = 4.86 μM) and U937 (8b, IC50 = 3.44 μM and 8c, IC50 = 1.65 μM) cells. Placing vanillin at position Ar2 further improved the potency when both compounds 15a and 15b significantly lowered the PGE2 secretion level (RAW264.7: 15a, IC50 = 0.78 μM and 15b, IC50 = 1.9 μM while U937: 15a, IC50 = 0.95 μM and 15b, IC50 = 0.92 μM). Further experiment showed that compounds 8b, 8c, 15a and 15b did not target the activity of downstream inflammatory COX-2 mediator. Finally, docking simulation on protein targets COX-2, IKK-β, ERK, JNK2, p38α and p38β were performed using the conformation of 15a determined by single-crystal XRD.

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