(Methoxyalkyl)thiazoles are novel 5-lipoxygenase (5-LPO) inhibitors that are neither redox agents nor iron chelators. Consideration of a hypothetical model of the enzyme active site led to this series which is exemplified by 1-[3-(naphth-2-ylmethoxy)phenyl]-1-(thiazol-2-yl)propy l methyl ether (2d, ICI211965). 2d inhibits cell-free guinea pig 5-LPO activity, LTC4 synthesis in plasma free mouse macrophages, and LTB4 synthesis in rat and human blood (IC50s 0.1 microM, 8 nM, 0.5 microM, and 0.4 microM, respectively) but does not inhibit the synthesis of cyclooxygenase products at concentrations up to 50 microM in macrophages and 100 microM in blood. 2d is orally active in rat (ex vivo ED50 10 mg/kg in blood taken in 1 h after dosing). SAR studies show that high in vitro potency requires methoxy, thiazolyl, and naphthyl groups and depends critically on the substitution pattern. (Methoxyalkyl)thiazoles are chiral. Resolution of 1-methoxy-6-(naphth-2-ylmethoxy)-1-(thiazol-2-yl)indan (2j, ICI216800) shows that (+)-2j is 50-150-fold more potent than (-)-2j in in vitro assays. Thus, (methoxyalkyl)thiazoles are a new series of orally active, selective 5-LPO inhibitors and represent the first class of inhibitors in which inhibition is mediated by specific, enantioselective interactions with the enzyme.

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The minor metabolites of both Pacific and Atlantic Ocean specimens of the cold water soft coral Gersemia rubiformis have been investigated. Pacific coast animals yielded two new pseudopterane diterpenoids, isogersemolides A (11) and B (12), and four new cembrane diterpenoids, isoepilophodiones A (13), B (14), and C (15) and rubifol(16). Atlantic coast animals yielded 3-acetoxy-P-cubebene (17 Chem. 66, 2928Chem. 66, (1988.On a examink les mitabolites mineurs d'kchantillons, provenant de l'ockan Atlantique ainsi que de l'ockan Pacifique, du corail mou vivant en eau froide Gersemia rubiformis. Les animaux du Pacifique ont fourni deux nouveaux diterpknoides du pseudoptirane, les isogerskmolides A (11) et B (12) ainsi que quatre nouveaux diterpkno'ides du cembrane, les isokpilophodiones A (13), B (14) et C (15) ainsi que le rubifol (16). Les animaux de 1'Atlantique ont fourni de 1'acCtoxy-3 P-cubCbtne (17). Les structures qui sont proposkes pour les mktabolites sont toutes basies sur des analyses spectroscopiques ainsi que sur des interconversions chimiques.[Traduit par la revue]Tropical reef environments, particularly in the Indo-Pacific, are populated by a large variety of soft corals. In contrast to the tropical diversity of soft corals, the cold waters off both the eastern and western Canadian coasts harbour an extremely limited number of soft coral species (I).Gersemia rubiformis, commonly referred to as the "sea from Canadian waters. Our previous chemical studies on G.4 raspberry", is one soft coral that can be collected in abundance (7) (4), the gersolane diterpenoid gersolide (8) (5), and the cuprane sesquiterpenoids tochuinyl acetate (9) and dihydrotochuinyl acetate (10) (6). Our continuing investigations of the minor metabolites of both east and west coast specimens of G . rubiformis have resulted in the isolation of six new diterpenoids, 11-16, from the Pacific animals, and one new sesquiterpenoid, 17, from the Atlantic animals. We now wish to report the +.lit< structures of these new G. rubiformis metabolites.n Pacific coast specimens Samples of G. rubiformis were collected by hand using SCUBA (-5 to -15 m) around the Gordon Islands off the northern tip of Vancouver Island. Freshly collected soft coral was immediately immersed in methanol and extracted at room temperature for 2-3 days. The organic soluble portion of the methanol extract was fractionated by sequential application of 'present silica gel flash, silica gel preparative thin-layer (tlc), radial thin-layer, and normal and reverse phase high performance (hplc) chromatographies to give pure metabolites.Isogersemolide A (11) was obtained from methanol as colourless needles (mp 121-124°C). It showed a parent ion in the HREIMS at 328.1669 daltons appropriate for a molecular formula of C20H2404 (AM = -0.6 mmu), identical to that of gersemolide (7). The 13C nrnr spectrum of 11 ( Table 2) showed resonances that could be assigned to eight olefinic carbons, two ketone carbonyls, and one lactone carbonyl. Six of the olefinic carbons and all three of t...

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Two new C26 steroid Δ1.4-dien-3-ones 5 and 6 with 12β oxygen functions have been isolated from the soft coral Gersemiarubiformis and their structures elucidated from their spectral data and chemical transformations.