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

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

  • Bioorg Med Chem Lett. 2016 May 15;26(10):2531-2538. doi: 10.1016/j.bmcl.2016.03.092.
Mohd Fadhlizil Fasihi Mohd Aluwi 1,  Kamal Rullah 2,  Bohari M Yamin 3,  Sze Wei Leong 4,  Mohd Nazri Abdul Bahari 4,  Sock Jin Lim 1,  Siti Munirah Mohd Faudzi 5,  Juriyati Jalil 1,  Faridah Abas 4,  Norsyahida Mohd Fauzi 1,  Nor Hadiani Ismail 6,  Ibrahim Jantan 1,  Kok Wai Lam 7
Affiliations

Affiliations

  • 1 Drug and Herbal Research Centre, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia.
  • 2 Drug and Herbal Research Centre, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia; Sekolah Tinggi Ilmu Farmasi Riau, Universitas Riau, Kampus Bina Widya, Km 12.5, Simpang Baru-Pekanbaru 28293, Indonesia.
  • 3 School of Chemical Sciences and Technology, Universiti Kebangsaan Malaysia, 43600 Bangi, Selangor, Malaysia.
  • 4 Laboratory of Natural Product, Institute of Bioscience, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia.
  • 5 Laboratory of Natural Product, Institute of Bioscience, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia; Department of Chemistry, Faculty of Science, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia.
  • 6 Atta-Ur-Rahman Institute for Natural Product Discovery, Universiti Teknologi MARA Kampus Puncak Alam, 42300 Puncak Alam, Selangor, Malaysia.
  • 7 Drug and Herbal Research Centre, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia. Electronic address: david_lam@ukm.edu.my.
PMID: 27040659 DOI: 10.1016/j.bmcl.2016.03.092
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=12.01μM and 8c, IC50=4.86μM) and U937 (8b, IC50=3.44μM and 8c, IC50=1.65μM) 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=0.78μM and 15b, IC50=1.9μM while U937: 15a, IC50=0.95μM and 15b, IC50=0.92μM). 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.

Keywords

Cyclooxygenase-2; Prostaglandin E(2); RAW264.7; Single-crystal XRD; U937; Unsymmetrical curcumin analogues.

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