Design, synthesis, and biological evaluation of conformationally constrained aci-reductone mimics of arachidonic acid.
An efficient and convergent synthesis has been developed for the production of 3,4-dihydroxy-5-[4-(2-((2Z)-hexenyl)phenyl)-3-(1Z)-but enyl]-2 (5H)-furanone (12d). This hydrophobic antioxidant is a stable conformationally constrained mimic of arachidonic acid (AA) (1) and its respective aci-reductone analogue (2). Pd(0)-catalyzed cross-coupling of 5-(3-butynyl)-3,4-dihydroxy-2(5H)-furanone (7) with 2-((2Z)-hexenyl)iodobenzene (8d) followed by Lindlar catalyzed hydrogenation produces 12d. Butynyl intermediate 7 is prepared from 2-(benzyloxy)-5-deoxyascorbic acid (15) by iodination (I2, PPh3, Imd), iodo substitution with lithium acetylide ethylenediamine complex (LiAEDA, HMPA, -5 degrees C), and benzyl group cleavage (Ac2O, Pyr, BCl3). The utility of this synthetic method was demonstrated by the synthesis of analogues 10e-k. Biological testing revealed that certain of these antioxidants inhibit both cyclooxygenase (COX) and 5-lipoxygenase (5-LO) with comparable efficacy as reported for aspirin and zileuton, respectively. The antioxidant activity of these aci-reductones, measured as a function of their inhibitory effect on CCl4-induced lipid peroxidation of hepatic microsomes, exceeds that produced by alpha-tocopherol. Synthetic routes and initial structure-activity relationships (SAR) for these novel mixed functioning antioxidants are presented.
Hopper
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OXIS International, Inc., Portland, Oregon 97217, USA.
Witiak
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Ziemniak
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D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D016718:Arachidonic Acid / Q000737:chemistry*; D002461:Cell Line, Transformed; D002467:Cell Nucleus / Q000378:metabolism; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D007202:Indicators and Reagents; D007527:Isoenzymes / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000502:physiology; D008315:Malondialdehyde; D008565:Membrane Proteins; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D016328:NF-kappa B / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship
D000975:Antioxidants; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007202:Indicators and Reagents; D007527:Isoenzymes; D008070:Lipopolysaccharides; D016859:Lipoxygenase Inhibitors; D008565:Membrane Proteins; D016328:NF-kappa B; D016718:Arachidonic Acid; D008315:Malondialdehyde; D001094:Arachidonate 5-Lipoxygenase; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat