The amyloid-␤ peptide (A␤) can generate cytotoxic oligomers, and their accumulation is thought to underlie the neuropathologic changes found in Alzheimer's disease. Known inhibitors of A␤ polymerization bind to undefined structures and can work as nonspecific aggregators, and inhibitors that target conformations that also occur in larger A␤ assemblies may even increase oligomerderived toxicity. Here we report on an alternative approach whereby ligands are designed to bind and stabilize the 13-26 region of A␤ in an ␣-helical conformation, inspired by the postulated A␤ native structure. This is achieved with 2 different classes of compounds that also reduce A␤ toxicity to cells in culture and to hippocampal slice preparations, and that do not show any nonspecific aggregatory properties. In addition, when these inhibitors are administered to Drosophila melanogaster expressing human A␤ 1-42 in the central nervous system, a prolonged lifespan, increased locomotor activity, and reduced neurodegeneration is observed. We conclude that stabilization of the central A␤ ␣-helix counteracts polymerization into toxic assemblies and provides a strategy for development of specific inhibitors of A␤ polymerization.amyloid fibrils ͉ neurodegenerative disease ͉ protein misfolding ͉ Alzheimer's disease A lzheimer's disease is a progressive neurodegenerative disorder that is characterized by cerebral extracellular amyloid plaques and intracellular neurofibrillary tangles (1). Classically, the amyloid cascade hypothesis (2) states that Alzheimer's disease is caused by fibril and plaque formation of amyloid-␤ peptide (A␤) in the central nervous system. More recently, the hypothesis has been modified to include A␤ assemblies of sizes intermediate to monomeric and fibrillar forms, which today are considered to be the main source of cytotoxicity (3). Such A␤ assemblies include low-number oligomers and larger assemblies known as protofibrils, globulomers, Alzheimer's disease diffusible ligands, or A␤*56 (4-7). A␤ is cleaved from an integral membrane protein, the amyloid ␤ precursor protein (A␤PP), predominantly as a 40-residue peptide (A␤ 1-40 ). In addition, a C-terminally elongated 42-residue version can be excised (A␤ 1-42 ); it is this longer variant that is the main constituent of parenchymal amyloid deposits (8).The link between A␤ aggregation and Alzheimer's disease implies that inhibitors of this process should be able to slow down disease progression. A number of low-molecular-mass A␤ aggregation inhibitors have been identified by use of screens of compound libraries as well as rational design strategies. The resulting inhibitors include such chemically diverse compounds as curcumin, inositol, and nicotine (9, 10). The screens have identified inhibitors of fibril formation that similarly to the rationally designed inhibitors are predicted to bind to A␤ in an elongated, ␤-strand-like conformation and prevent its polymerization. A potential problem with this strategy is that blocking the later stages of fibril formation will favor t...

Into the pot: A one‐pot highly chemo‐ and enantioselective catalytic domino oxa‐Michael/carbocyclization between α,β‐unsaturated aldehydes and propargylic alcohols is presented. This dynamic kinetic transformation requires a combination of transition‐metal and amine catalysis to afford functionalized dihydrofurans in good to high yields and up to 99.5:0.5 e.r.

Enol MEM ethers 4 and 15 and the corresponding enol acetates were hydrogenated over Pd/C with very high (>99%) diastereoselectivity to saturated delta-lactones. A stereochemical generalization can be formulated thus: trans-5,6-disubstituted 1-oxa-3-cyclohexen-2-ones (e.g. 14 and 15) are hydrogenated over Pd with high selectivity from the side trans to the C(6)-substituent. A mechanistic rationalization of the stereochemical outcome in the Pd-catalyzed hydrogenation of this as well as other types of substituted alpha,beta-unsaturated delta-lactones is presented. An analysis of X-ray crystallographic data for 67 compounds demonstrated a great conformational diversity of the saturated delta-lactone ring. Besides, ab initio calculations (HF/6-31G) indicated a very high conformational mobility. Thus, the lowest calculated transition state for the conversion of the half-chair, most stable, conformer of delta-valerolactone to the boat-type conformer lies only 1.93 kcal/mol above the former. Beside these two conformers, also chair, envelope and skew conformations are accessible; all lie less than 2 kcal/mol above the half-chair. The previous conformational paradigm comprising only boat and half-chair types is incomplete.

The lack of efficient in vivo gene delivery is a well-known shortcoming of nonviral delivery vectors, in particular of chemical vectors. We developed a series of novel nonviral carriers for plasmid-based in vivo gene delivery. This new transport device is based on the assembly of DNA plasmids with synthetic derivatives of naturally occurring moleculesfatty acid-spermine conjugates (or lipospermines). We tested the ability of these fatty acid conjugates to interact with plasmid DNA (pDNA) and found that they formed DNA nanocomplexes, which are protected from DNase I degradation. This protection was shown to directly correlate with the length of the aliphatic component. However, this increase in the length of the hydrocarbon chain resulted in increased toxicity. The cationic lipids used for transfection typically have a C 16 and C 18 hydrocarbon chain. Interestingly, toxicity studies, together with further characterization studies, suggested that the two most suitable candidates for in vivo delivery are those with the shortest hydrocarbon chain, butanoyl-and decanoylspermine. Morphological characterization of DNA nanocomplexes resulting from these lipospermines showed the formation of a homogenous population, with the diameter ranging approximately from 40 to 200 nm. Butanoylspermine was found to be the most promising carrier from this series, resulting in a significantly increased gene expression, in relation to naked plasmid, in both tissues herein targeted (dermis and M. tibialis anterior). Thus, we established a correlation between the in vitro properties of the ensuing DNA nanocarriers and their efficient in vivo gene expression.