title: Synthesis of unsymmetrical monocarbonyl curcumin analogues with potent inhibition on prostaglandin E2 production in LPS-induced murine and human macrophages cell lines.
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.
authors.affiliation: Drug and Herbal Research Centre, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia.
authors.forename: Mohd Fadhlizil Fasihi
authors.initials: MFF
authors.lastname: Mohd Aluwi
authors.affiliation: 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.
authors.forename: Kamal
authors.initials: K
authors.lastname: Rullah
authors.affiliation: School of Chemical Sciences and Technology, Universiti Kebangsaan Malaysia, 43600 Bangi, Selangor, Malaysia.
authors.forename: Bohari M
authors.initials: BM
authors.lastname: Yamin
authors.affiliation: Laboratory of Natural Product, Institute of Bioscience, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia.
authors.forename: Sze Wei
authors.initials: SW
authors.lastname: Leong
authors.affiliation: Laboratory of Natural Product, Institute of Bioscience, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia.
authors.forename: Mohd Nazri
authors.initials: MN
authors.lastname: Abdul Bahari
authors.affiliation: Drug and Herbal Research Centre, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia.
authors.forename: Sock Jin
authors.initials: SJ
authors.lastname: Lim
authors.affiliation: 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.
authors.forename: Siti Munirah
authors.initials: SM
authors.lastname: Mohd Faudzi
authors.affiliation: Drug and Herbal Research Centre, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia.
authors.forename: Juriyati
authors.initials: J
authors.lastname: Jalil
authors.affiliation: Laboratory of Natural Product, Institute of Bioscience, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia.
authors.forename: Faridah
authors.initials: F
authors.lastname: Abas
authors.affiliation: Drug and Herbal Research Centre, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia.
authors.forename: Norsyahida
authors.initials: N
authors.lastname: Mohd Fauzi
authors.affiliation: Atta-Ur-Rahman Institute for Natural Product Discovery, Universiti Teknologi MARA Kampus Puncak Alam, 42300 Puncak Alam, Selangor, Malaysia.
authors.forename: Nor Hadiani
authors.initials: NH
authors.lastname: Ismail
authors.affiliation: Drug and Herbal Research Centre, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia.
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Jantan
authors.affiliation: 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.
authors.forename: Kok Wai
authors.initials: KW
authors.lastname: Lam
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D060326:Chemistry Techniques, Synthetic; D018360:Crystallography, X-Ray; D003474:Curcumin / Q000031:analogs & derivatives* / Q000737:chemistry; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D051550:I-kappa B Kinase / Q000737:chemistry / Q000378:metabolism; D020128:Inhibitory Concentration 50; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D048056:Mitogen-Activated Protein Kinase 9 / Q000737:chemistry / Q000378:metabolism; D062105:Molecular Docking Simulation
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D008070:Lipopolysaccharides; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D048056:Mitogen-Activated Protein Kinase 9; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; D003474:Curcumin; D015232:Dinoprostone
keywords: Cyclooxygenase-2; Prostaglandin E(2); RAW264.7; Single-crystal XRD; U937; Unsymmetrical curcumin analogues