title: Inhibition of prostaglandin E(2) production by synthetic minor prenylated chalcones and flavonoids: synthesis, biological activity, crystal structure, and in silico evaluation.
abstract: The discovery of potent inhibitors of prostaglandin E2 (PGE2) synthesis in recent years has been proven to be an important game changer in pharmaceutical industry. It is known that excessive production of PGE2 triggers a vast array of biological signals and physiological events that contributes to inflammatory diseases such as rheumatoid arthritis, atherosclerosis, cancer, and pain. In this Letter, we report the synthesis of a series of minor prenylated chalcones and flavonoids which was found to be significantly active in suppressing the PGE2 production secreted by lipopolysaccharide-induced mouse macrophage cells (RAW 264.7). Among the compounds tested, 14b showed a dose-response inhibition of PGE2 production with an IC50 value of 2.1 μM. The suppression upon PGE2 secretion was not due to cell death since 14b did not reduce the cell viability in close proximity to the PGE2 inhibition concentration. The obtained atomic coordinates for the single-crystal XRD of 14b was then applied in the docking simulation to determine the potential important binding interactions with murine COX-2 and mPGES-1 putative binding sites.
authors.affiliation: Drugs 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, Indonesia.
authors.forename: Kamal
authors.initials: K
authors.lastname: Rullah
authors.affiliation: Drugs 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: MF
authors.lastname: Mohd Aluwi
authors.affiliation: School of Chemical Sciences and Food Technology, Universiti Kebangsaan Malaysia, 43600 Bangi, Selangor, Malaysia.
authors.forename: Bohari M
authors.initials: BM
authors.lastname: Yamin
authors.affiliation: Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia.
authors.forename: Mohd Nazri
authors.initials: MN
authors.lastname: Abdul Bahari
authors.affiliation: Institute of Bioscience, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia.
authors.forename: Leong Sze
authors.initials: LS
authors.lastname: Wei
authors.affiliation: Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia.
authors.forename: Syahida
authors.initials: S
authors.lastname: Ahmad
authors.affiliation: Institute of Bioscience, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia.
authors.forename: Faridah
authors.initials: F
authors.lastname: Abas
authors.affiliation: Faculty of Science, Universiti Teknologi MARA, 50400 Shah Alam, Selangor, Malaysia.
authors.forename: Nor Hadiani
authors.initials: NH
authors.lastname: Ismail
authors.affiliation: Drugs 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: Drugs and Herbal Research Centre, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia. Electronic address: david_lam_98@yahoo.com.
authors.forename: Lam Kok
authors.initials: LK
authors.lastname: Wai
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D047188:Chalcones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D005419:Flavonoids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D000071876:Prostaglandin-E Synthases; D013329:Structure-Activity Relationship
chemical_list: D047188:Chalcones; D005419:Flavonoids; D008070:Lipopolysaccharides; D051546:Cyclooxygenase 2; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D015232:Dinoprostone
keywords: ADMET prediction; COX-2 inhibitor; Minor flavonoids; Prenylated chalcone; Prostaglandin E(2); Single-crystal XRD