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Long-term macrolide therapy has been proven to improve survival in patients with diffuse panbronchiolitis. Although its mechanisms remain unknown, previous studies have suggested the effects of macrolide might be anti-inflammatory rather than antibacterial. To elucidate the molecular mechanisms of its action, we studied here the effects of erythromycin (EM) and its new derivative, EM703, which shows no antibacterial action, on the activation of the transcription factor nuclear factor-B (NF-B) in human bronchial epithelial cells. Western blotting analysis showed that EM did not inhibit the degradation of IB␣, suggesting the molecular target for EM was not the dissociation of NF-B from IB. An electrophoretic mobility shift assay showed that EM did not interrupt the NF-B DNA-binding activity in the nucleus under the conditions tested. Moreover, not only EM but also EM703 suppressed the activation of NF-B and the production of interleukin-8, demonstrating that the anti-inflammatory action of the macrolide is independent of its antibacterial activity. Taken together, these data suggest EM has an anti-inflammatory action, presumably via an interaction with the NF-B signaling pathway in the downstream of the dissociation from IB, resulting in the inhibition of NF-B.

After 50 years of persistence the 12‐membered cyclic skeleton of bottromycin A2 (3) has been confirmed by NMR experiments (HMBC), and the configurations of two tLeu residues have been estimated by conformation analysis and NMR experiments. Furthermore, the key step in the synthesis of 3 involves the mercury‐mediated formation of the amidine of thioamide 1 and amine 2.

, which have a fuloindoline structure with diketocyclopentene bound to the methyl group. MDL-A has no cytotoxic activities. It inhibited only activities of both IL-6 and IL-11 without affecting the IL-6-specific signal transduction cascade, JAK2͞STAT3. In a dose-dependent manner [ 3 H]MDL-A binds to gp130, which is a signal transducing 130-kDa glycoprotein, but formation of the trimeric complex IL-6͞IL-6 receptor͞gp130 was not inhibited, suggesting that MDL-A suppresses dimerization of trimeric complexes. Not only did MDL-A markedly inhibit IL-6-and IL-11-induced osteoclastogenesis in vitro, but it also inhibited IL-6-stimulated serum amyloid A production and bone resorption in an experimental model of postmenopausal osteoporosis in vivo by a different mechanism from that of 17␤-estradiol. Here we show that MDL-A has a highly selective inhibitory effect on IL-6 and IL-11 activities by inhibiting a gp130 activity while suppressing bone loss in ovariectomized mice. MDL-A is anticipated as a lead compound for treatment of hormone-dependent postmenopausal osteoporosis, which has no serious side effects, and as a new mechanism of action, gp130 blocking.

The mutant of Penicillium sp. FO-4259, an arisugacins A and B producing strain, was found to produce a series of metabolites, designated arisugacins C, D, E, F, G and H, which were structurally related to arisugacins A and B. These compoundswere isolated from the culture broth and the physico-chemical and biological properties were examined. The IC50

The structures of newprotein farnesyltransferase inhibitors, andrastins A~C, were elucidated. Thecyclopentane ring of andrastins exhibited keto-enol tautomerism, whichmadethe structure hard to elucidate. Therefore, the structure of andrastin A was elucidated by INADEQUATE and 13C-1 3C couplings using 1 3C-labeled andrastin A. The absolute configuration of the />-bromobenzoyl derivative of andrastin A was elucidated by X-ray crystallographic analysis and its skeleton was shownto be enr-5a,14/?-androstane. The biosynthesis of andrastin A was also studied by the incorporation of 13C-labeled acetates. Though the andrastins had a commonandrostane skeleton, they were biosynthesized from a sesquiterpene and a tetraketide.

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