Cerebral deposition of beta-amyloid protein is a pathological feature central to Alzheimer's disease. Production of beta-amyloid by proteolytic processing of the beta-amyloid precursor protein (beta APP) is a critical initial step in beta-amyloidogenesis. We use an inhibitor of beta APP processing to block beta-amyloid peptide formation. Application of the inhibitor to cultured cells results in an accumulation of proteolytic intermediates of beta APP, enabling a precursor-product relationship between beta APP carboxy-terminal fragments and beta-amyloid peptides to be demonstrated directly. In the presence of inhibitor, these amyloidogenic carboxy-terminal fragments can be degraded to nonamyloidogenic products. The catabolism of beta APP carboxy-terminal intermediates and the formation of beta-amyloid peptides are likely to involve an early endosomal compartment as the subcellular site of processing.
SummaryWe describe the development and characterization of a mouse and human epithelial cell monolayer platform of the small and large intestines, with a broad range of potential applications including the discovery and development of minimally systemic drug candidates. Culture conditions for each intestinal segment were optimized by correlating monolayer global gene expression with the corresponding tissue segment. The monolayers polarized, formed tight junctions, and contained a diversity of intestinal epithelial cell lineages. Ion transport phenotypes of monolayers from the proximal and distal colon and small intestine matched the known and unique physiology of these intestinal segments. The cultures secreted serotonin, GLP-1, and FGF19 and upregulated the epithelial sodium channel in response to known biologically active agents, suggesting intact secretory and absorptive functions. A screen of over 2,000 pharmacologically active compounds for inhibition of potassium ion transport in the mouse distal colon cultures led to the identification of a tool compound.
Heat shock protein 90 (Hsp90) is a molecular chaperone with many oncogenic client proteins. The small-molecule Hsp90 inhibitor alvespimycin, a geldanamycin derivative, is being developed for various malignancies. This phase 1 study examined the maximum-tolerated dose (MTD), safety and pharmacokinetic/pharmacodynamic profiles of alvespimycin in patients with advanced acute myeloid leukemia (AML). Patients with advanced AML received escalating doses of intravenous alvespimycin (8-32 mg/m 2 ), twice weekly, for 2 of 3 weeks. Dose-limiting toxicities (DLTs) were assessed during cycle 1. A total of 24 enrolled patients were evaluable for toxicity. Alvespimycin was well tolerated; the MTD was 24 mg/m 2 twice weekly. Common toxicities included neutropenic fever, fatigue, nausea and diarrhea. Cardiac DLTs occurred at 32 mg/m 2 (elevated troponin and myocardial infarction). Pharmacokinetics revealed linear increases in C max and area under the curve (AUC) from 8 to 32 mg/m 2 and minor accumulation upon repeated doses. Pharmacodynamic analyses on day 15 revealed increased apoptosis and Hsp70 levels when compared with baseline within marrow blasts. Antileukemia activity occurred in 3 of 17 evaluable patients (complete remission with incomplete blood count recovery). The twiceweekly administered alvespimycin was well tolerated in patients with advanced AML, showing linear pharmacokinetics, target inhibition and signs of clinical activity. We determined a recommended phase 2 dose of 24 mg/m 2 .
6187 determination summary of [TTF] [(CHz),Tcbiim] including tables of bond lengths and bond angles, tables of atomic positions and thermal parameters, and additional crystal-packing diagrams and an ORTEP plot of [TTF][(CH2)zTcbiim] (14 pages): tables of structure factors for C18HsNsS4 (10 pages). Ordering information is given on any current masthead page. helpful discussions and suggestions. We especially thank Professor A. H. Francis and S. Sibley for luminescence spectroscopy measurements. We also thank Dr. J. Kampf for the X-ray crystallography.Abstract: A combined fructose 1,6diphosphate aldolase reaction and catalytic reductive amination has been used in the asymmetric synthesis of azasugars structurally corresponding to N-acetylglucosamine, N-acetylmannosamine, and deoxyhexoses. The 6-deoxyazasugars were prepared by direct hydrogenolysis of the aldolase product without removal of the 6-phosphate group.Both (R)and (S)-3-azido-2-acetamidopropanal used as substrates in the aldolase reactions were prepared from the corresponding lipase-resolved 2-hydroxy species followed by formation of an aziridine intermediate and opening of the aziridine with azide. Evaluation of these azasugars and their diastereomerically pure tertiary amine oxides as well as 5-thioglucose and its sulfoxide derivatives as glycosidase inhibitors was carried out. It was found that all synthetic azasugars and 5-thioglucose were strong inhibitors, but oxidation of the ring heteroatom weakened the inhibition. With the aid of molecular modeling and inhibition analysis, a structure-K; relation of inhibitors was established which provides useful information for the design of new glycosidase inhibitors.Many pyranoses and furanoses with the ring oxygen replaced by an imino group are natural products and useful as potent glycosidase inhibitorse2 This discovery has stimulated interests in the development of effective procedures for the synthesis of various azasugars' and analogues4 for the investigation of glycosidase reactions5 and the development of specific glycosidase ~ ~~ ~~~ ____ (1) Supported by the NIH (GM44154). (2) (a) Paulsen, H.; Tcdt, K. Petursson, S.; Campbell, A. L.; Mueller, R. A.; Behling, J. R.; Babiak, K. A,; Ng, J. S.; Scaros, M. G. J. Chem. Soc., Perkin Trans. 1989,665. (I) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Merino, P.
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