We describe the synthesis and biological evaluation of N-aryl-5-aryloxazol-2-amine derivatives that are able to inhibit 5-lipoxygenase (5-LOX), a key enzyme of leukotriene synthesis, for the treatment of inflammation-related diseases including asthma and rheumatoid arthritis. A novel structural moiety containing oxazole was initially identified from a chemical library using an in vitro enzymatic and cell-based assay, and its synthesized oxazole derivatives were further examined to develop a structure-activity relationship (SAR). SAR analysis demonstrated that a hydroxyl or amino group at the p-position on N-phenyl was essential for the 5-LOX-inhibitory activities of the derivatives, and that other halogen and methyl group-substituted derivatives affected the potency, positively or negatively. As a result, derivatives selected through first-round screening were further optimized using a cell-based assay and an in vivo assay to develop a potent, selective 5-LOX inhibitor. A final hit exhibited an improved efficacy in arachidonic acid-induced ear edema when applied topically but not orally. Moreover, it showed the additional advantage of sustainable antiinflammatory activity over a reference compound, zileuton. Taken together, chemical entities bearing an oxazole scaffold could be promising as therapeutic drugs for the treatment of chronic inflammatory skin disorders.Key words 5-lipoxygenase; antiinflammatory activity; oxazol-2-amine; leukotriene In response to external stresses, several enzymes are involved in the production of inflammatory chemical mediators from arachidonic acid (AA) that is released from the cytoplasmic membrane.1) Specifically, prostaglandins (PGs) and leukotrienes (LTs) are, respectively, formed from an AA substrate, catalyzed by two individual enzymes, cyclooxygenase (COX) and lipoxygenase (LOX), at the bifurcation of the metabolic pathway.2,3) Initial approaches targeting COX-2 selectively in an effort to develop anti-inflammatory drugs proved to be inappropriate due to their adverse cardiac effects. 4) Alternative ways to control inflammatory mediators have been pursued for the treatment of inflammation-related diseases. The 5-lipoxygenase (5-LOX) is a key enzyme in the first step of leukotriene (LT) synthesis, and its dysregulation causes various inflammatory diseases, such as atopy and asthma.5,6) Among the LTs, leukotriene B4 (LTB4) is a key chemoattractant for neutrophils recruitment, a hallmark of acute inflammation 7) and the others, termed collectively the "cysteinyl LTs," act as the slowly reacting substances of anaphylaxis. 8)Thus, 5-LOX inhibitors that are able to block LTs production could be effective therapeutic agents to treat inflammatory diseases. Presently, only zileuton has been approved by the Food and Drug Administration (FDA) as a direct 5-LOX inhibitor. 9) However, there are many anti-inflammatory drugs based on the abrogation of the ligand-receptor interaction or indirect interference in the process of 5-LOX activation. [10][11][12] Recently, there has been special i...

No abstract

±)-Filiforminol and (±)-bromoether A, marine halogenated sesquiterpenes, were synthesized in a concise manner from 3-methylcyclopent-2-en-l-one using copper-catalyzed conjugate addition and subsequent methylation, epoxidation, and spontaneous cyclization as key synthetic steps.A number of halogenated sesquiterpenes with the cuparane or the rearranged cuparane skeleton have been isolated from the red alga Laurencia and also from the sea hare Aplysia species. 1 Among them, filiforminol (1) was iso]ated from the red alga L. filiformis 2 and bromoether A (2) was isolated from L. grandulifera 3 and L. nana. 4 These sesquiterpenes represent a new structural type, and some of them also show important biological activity, such as antifungal and antibiotic properties.The relative stereochemistry was determined on the basis of the 1 H NMR chemical shifts and NOE data. The chemical shift of the 2-methyl doublet (d = 0.68) of the trans isomer was shielded relative to that of the methyl doublet (d = 1.03) of the cis isomer. 9 Strong NOE to the 2-H was observed after irradiation of the 3-methyl group in the trans isomer while no NOE was observed in the cis isomer. O OH Br H O Br Br H 2 1The structural uniqueness and the interesting bioactivities prompted us to investigate the total synthesis of these natural products 5 and in this report we describe a stereocontrolled synthesis of (±)-filiforminol and (±)-bromoether A.The structural features include a trichothecane-like skeleton 6 with two vicinal methyl groups in trans orientation. Our approach to filiforminol involves opening of epoxide compound 3, which is derived from debromoallolaurinterol (4) resulting from demethylation of compound 5. Compound 5 can be prepared from readily available 3-methylcyclopent-2-en-1-one (7) using copper-catalyzed conjugate addition of Grignard reagent and subsequent methylation, followed by methylenation. The retrosynthetic scheme based on this strategy is shown in Scheme 1.Our synthesis started with 3-methylcyclopent-2-en-1-one (7) (Scheme 2). A conjugate addition of the Grignard reagent 8 derived from 2-bromo-5-methylanisole 7 in the presence of cuprous ions in THF at 0°C produced the enolate. Subsequent addition of excess iodomethane in HMPA at 0°C and warming to room temperature gave the desired trans-3-(2-methoxy-4-methylphenyl)-2,3-dimethylcyclopentanone (6) and cis isomer 9 in a ratio of 2.8:1 along with nonmethylated compound 10. 8 OH OH OMe O OMe M OMe O O OH Br H O 3 + 4 5 6 7

No abstract

No abstract