1 Fibril formation of amyloid b peptide (Ab) is considered to be responsible for the pathology of Alzheimer's disease (AD). The Ab ®bril is formed by a protein misfolding process in which intermolecular b-sheet interactions become stabilized abnormally. Thus, to develop potential anti-AD drugs, we screened an in-house library to ®nd compounds which have a pro®le as a b-sheet breaker.2 We searched for a b-sheet breaker pro®le in an in-house library of approximately 113,000 compounds. From among the screening hits, we focused on N,N'-bis(3-hydroxyphenyl)pyridazine-3,6-diamine (named RS-0406), which had been newly synthesized in our laboratory. This compound (10 ± 100 mg ml 71 ) was found to be capable of signi®cantly inhibiting 25 mM Ab 1 ± 42 ®brillogenesis and, furthermore, disassembling preformed Ab 1 ± 42 ®brils in vitro. 3 We then investigated the e ect of RS-0406 on 111 nM Ab 1 ± 42 -induced cytotoxicity in primary hippocampal neurons, and found that 0.3 ± 3 mg ml 71 RS-0406 ameliorates the cytotoxicity. Moreover, 3 mg ml 71 RS-0406 reversed 1 mM Ab 1 ± 42 -induced impairment of long-term potentiation in hippocampal slices. 4 In this study, we have succeeded in identifying RS-0406 which has potential to inhibit Ab 1 ± 42 ®brillogenesis, and to protect neurons against Ab 1 ± 42 -induced biological toxicity in vitro. These results suggest that RS-0406 or one of the derivatives could become a therapeutic agent for AD patients.
[formula: see text] The segment-coupling Prins cyclization avoids two of the problems common to other Prins cyclization protocols: side-chain exchange and partial racemization by reversible 2-oxonia Cope rearrangement. Model studies demonstrate the stereochemical fidelity of Prins cyclizations using alpha-acetoxy ethers compared with direct aldehyde-alcohol Prins reactions. Furthermore, we propose a mechanism for the racemization observed in some intermolecular Prins cyclizations. Two straightforward syntheses of optically pure (-)-centrolobine highlight the utility of Prins cyclizations.
[reaction--see text] The 2-oxonia Cope rearrangement is undetectable in typical Prins cyclization reactions. We have investigated the Cope rearrangement in a Prins cyclization reaction using a competitive reduction of the oxocarbenium ion intermediate, and a racemization reaction mediated by the rearrangement. In our unactivated substrate, the 2-oxonia Cope rearrangement was much faster than Prins cyclization. An enantioselective allyl transfer reaction also was developed using a 2-oxonia Cope rearrangement.
The synthesis and absolute configuration of SCH 351448, an interesting ionophoric natural product, are reported herein. Mukaiyama aldol-Prins and segment-coupling Prins reactions were employed to construct the constituent tetrahydropyrans of SCH 351448. Efforts to assemble the C2-symmetric core of the natural product by a templated olefin metathesis strategy are described; however, a stepwise fragment assembly was ultimately utilized to complete the target molecule.
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