title: Synthesis and anti-inflammatory properties of some aromatic and heterocyclic aromatic curcuminoids.
abstract: A variety of novel aromatic and heterocyclic aromatic curcuminoids were synthesised, characterised and their anti-inflammatory activities (AIA) determined in vivo. Some of these compounds also were tested for inflammatory mediator production. The AIA of the main representatives of these compounds were assessed by oral administration to female Wistar rats using (a) acute carrageenan-induced paw oedema, (b) chronic adjuvant arthritis (therapeutic mode), and (c) anti-pyretic activity assessed in the yeast pyrexia. Gastric ulceration was determined in pre-inflamed rats. Natural curcumin showed modest aspirin-like anti-inflammatory activity which was enhanced when co-administered with the PGE(1) analogue misoprostol as a synergist. In contrast, four novel curcuminoids (RK-97, RK-103, RK-104 and RK-106) in which the bis-methoxy-phenyl group of curcumin was replaced with bis-dimethoxybutenolidyl-(ascorbate), bis-naphthyl, and bis-furanyl derivatives, respectively, had potent activity in the anti-arthritic assay with little gastric or systemic toxicity, compared with the vehicle-treated controls. Of the curcuminoids the furan RK-106 was the only compound to inhibit production of TNFα and IL-1β in a monocytic cell-line THP-1 in vitro. The inactivity of RK-106 on the production of PGE(2) may be related to its absence of gastrotoxicity. None of the curcuminoids exhibited anti-pyretic activity and this may also be related to its insensitivity to PGE(2). Thus, these novel curcuminoids, such as RK-106, may warrant the development of new low gastro-toxic anti-inflammatory agents with selective inhibitory activity of cytokine inflammatory mediators.
authors.affiliation: Biomedical Research Centre, Sheffield Hallam University, Howard Street, Sheffield S11WB, UK. Electronic address: m.a.khan@shu.ac.uk.
authors.forename: M Akram
authors.initials: MA
authors.lastname: Khan
authors.affiliation: Biomedical Research Centre, Sheffield Hallam University, Howard Street, Sheffield S11WB, UK.
authors.forename: Riyad
authors.initials: R
authors.lastname: El-Khatib
authors.affiliation: Biomedical Research Centre, Sheffield Hallam University, Howard Street, Sheffield S11WB, UK; Therapeutics Research Unit, Department of Medicine, University of Queensland, Princess Alexandra Hospital, Buranda, Queensland 4102, Australia.
authors.forename: K D
authors.initials: KD
authors.lastname: Rainsford
authors.affiliation: Therapeutics Research Unit, Department of Medicine, University of Queensland, Princess Alexandra Hospital, Buranda, Queensland 4102, Australia.
authors.forename: M W
authors.initials: MW
authors.lastname: Whitehouse
mesh_terms: D000284:Administration, Oral; D000527:Alprostadil / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000494:pharmacology; D001169:Arthritis, Experimental; D002351:Carrageenan / Q000633:toxicity; D002460:Cell Line; D003474:Curcumin / Q000031:analogs & derivatives* / Q000494:pharmacology; D004487:Edema / Q000139:chemically induced; D005260:Female; D006571:Heterocyclic Compounds / Q000737:chemistry*; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D006571:Heterocyclic Compounds; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D002351:Carrageenan; D000527:Alprostadil; D003474:Curcumin