A prolonged or excessive adrenergic activation leads to myocyte loss and heart dysfunction; however, how it contributes to heart failure remains poorly defined. Here we show that isoproterenol (ISO) induced aberrant endoplasmic reticulum (ER) stress and apoptotic cell death, which was inhibited by activating the AMP-activated protein kinase (AMPK) in vitro and in vivo. Persistent ISO stimulation suppressed the AMPK phosphorylation and function, resulting in enhanced ER stress and the subsequent cell apoptosis in cardiomyocytes in vitro and in vivo. AMPK activation decreased the aberrant ER stress, apoptosis, and brain natriuretic peptide (BNP) release in ISO-treated cardiomyocytes, which was blocked by AMPK inhibitor Compound C. Importantly, increased ER stress and apoptosis were observed in ISO-treated cardiomyocytes isolated from AMPKα2(-/-) mice. Inhibition of ER stress attenuated the apoptosis but failed to reverse AMPK inhibition in ISO-treated cardiomyocytes. Moreover, metformin administration activated AMPK and reduced both ER stress and apoptosis in ISO-induced rat heart failure in vivo. We conclude that ISO, via AMPK inactivation, causes aberrant ER stress, cardiomyocyte injury, BNP release, apoptosis, and hence heart failure in vivo, all of which are inhibited by AMPK activation.

The effect of introducing hydrophobic groups onto the disaccharide portion of the mannopeptimycins has been examined. Under acid-catalyzed conditions dimethyl acetals and ketals react on the terminal mannose of the disaccharide moiety of mannopeptimycin-alpha and the cyclohexylalanyl analogue 2. The preferentially formed monofunctionalized 4,6-acetals and -ketals display potent antibacterial activities against Gram-positive microorganisms, including MRSA, PRSP, and VRE pathogens.

No abstract

The bifunctional 2-cyclohexenone that is produced by addition of the Grignard reagent derived from 6-chloro-2-hexyne to 3-ethoxycyclohexenone was irradiated.[ 2+2] Cycloaddition occurred to produce a highly sensitive tricyclic cyclobutene (14), which underwent ready double-bond migration in the presence of palladium(I1) acetate. With the exocyclic a bond in position, the a,&unsaturated ketone functionality was next elaborated. Although oxidation of 15 via organoselenium methodology did give 16, the yield was only modest. A more expedient approach involved initial conversion of 14 to its silyl enol ether and concurrent oxidation-olefin isomerization with Pd(I1). Hydride reduction of the resulting dienone proceeded stereospecifically to deliver an allylic alcohol that underwent smooth dehydration to give the target hydrocarbon 11 when treated with 2,4-dinitrobenzenesulfenyl chloride and triethylamine. The available evidence suggests that disrotatory ring opening within intermediate 18 occurs readily.Although studies of the chemical reactivity of 7-methylene-1,3,5-cyclooctatrienes are sparse, it is already clear that this class of polyolefins offers the potential for inspiring considerable physical-organic and synthetic research. Gream has demonstrated, for example, that 1, the a 0 x-Y --2 4 -5 6 parent member of the series, enters into reaction with highly reactive dienophiles (e.g., tetracyanoethylene) and uniparticulate electrophiles' (e.g., chlorosulfonyl isocyanate) to give structurally novel adducts of type 2 and/or 3.2 This behavior, which is shared by 4 and 5, is construed to be indirect evidence for the intervention of functionalized homotropylium zwitterions typified by 6. Whereas charge annihilation at C-7 yields [8+2] adducts 2, covalent bond formation at C-2 leads to cyclopropyl products structurally akin to 3.Progress in this area has been limited by the synthetic accessibility of 7-methylene-l,3,5-cyclooctatriene derivatives. Tetraene 1, which is available by appropriate Wittig condensation of cycloocta-2,4,6-trienone with methylenetriphenylph~sphorane,~ may be classified as readily available. However, neither position-specific derivatives of 1 nor annulated homologues of this ring system are as easily acquired. To illustrate, hydrocarbons 4 and 5 are produced (in varying yields and purity depending on solvent) during solvolysis of w-cyclooctatetraenylalkanesulfonate ester^.^^^ No other synthetic entry is presently available.In connection with another research objective, we considered the retrosynthetic analysis summarized in Scheme (1) Paquette, L. A.; Allen, G. R., Jr.; Broadhurst, M. J. J. Am. Chem. (2) Ferber, P. H.; Gream, G. E.; Kirkbride, P. K. Tetrahedron Lett. (3) See footnote 1 of ref 2. (4) (a) Gream, G. E.; Mular, M. Aust. J. Chem. 1975, 28, 2227. (b) Ferber, P. H.; Gream, G. E.; Wagner, R. D. Ibid. 1980, 33, 1569. (5) (a) Kitching, W.; Henzel, K. A.; Paquette, L. A. J. Am. Chem. SOC. 1975, 97, 4643. (b) Paquette, L. A.; Henzel, K. A. Ibid. 1975, 97, 4649.

The chiral 1,3‐bridged cyclooctatetraene (Xa) is synthesized in nine steps starting from the cyclododecenone (I).