Total Synthesis of the Proposed Structure of Paraphaeosphaeride C.

Paraphaeosphaeride C is a demethoxy derivative of phaeosphaeride A and exhibits STAT3 inhibitory activity. Our previous papers reported the total synthesis of phaeosphaeride A using a diastereoselective vinyl anion aldol reaction as the key step to construct the dihydropyran ring. In this work, the first total synthesis of the proposed structure of paraphaeosphaeride C was achieved via a similar synthetic strategy. The synthetic compound was characterized through extensive nuclear magnetic resonance (NMR) analysis but the 1H and 13C-NMR data for this compound did not correspond to those reported in the literature for paraphaeosphaeride C.

Total Synthesis of Highly Oxygenated Bisabolane Sesquiterpene Isolated from Ligularia lankongensis: Relative and Absolute Configurations of the Natural Product.

The relative and absolute configurations of an oxygenated bisabolane natural product, isolated from Ligularia lankongensis, were determined by synthesis. All four possible stereoisomers and their tiglate analogues were synthesized from R-(-)-carvone, and their 1H and 13C NMR spectra were compared to establish the 6R,8S,10S configuration. The stereoselective synthesis of the natural product was also achieved, featuring Brown allylation, vanadium-catalyzed epoxidation, and the Mitsunobu reaction.

Establishment of relative and absolute configurations of phaeosphaeride A: total synthesis of ent-phaeosphaeride A.

The relative and absolute configurations of phaeosphaeride A have been established via the first total synthesis of ent-phaeosphaeride A. The three contiguous stereogenic centers were installed by Sharpless asymmetric dihydroxylation and a stereoselective intramolecular vinyl anion aldol reaction. This synthesis has altered the originally proposed structure of natural phaeosphaeride A.

Improved preparation of methyl bis(2,2,2-trifluoroethoxy)-bromophosphonoacetate for the stereoselective synthesis of (E)-α-bromoacrylates.

We have established an efficient method for preparing methyl bis(2,2,2-trifluoroethoxy)bromophosphonoacetate, which we developed for the stereoselective synthesis of (E)-α-bromoacrylates. This improved method enables the reagent to be prepared reproducibly in one step from methyl bis(2,2,2-trifluoroethoxy)phosphonoacetate.

Enantioselective total synthesis of (+)-rubrobramide, (+)-talaramide A, and (-)-berkeleyamide D by a skeletal diversification strategy.

A unified synthesis of (+)-rubrobramide, (+)-talaramide A, and (-)-berkeleyamide D was achieved from the vinylogous esters by a skeletal diversification strategy based on regioselective 5-exo or 6-endo cyclization. This report describes the first enantioselective total synthesis of (+)-rubrobramide and (+)-talaramide A. Additionally, synthetic spirocyclic lactam compounds, including (-)-berkeleyamide D, showed moderate inhibitory activity against amyloid-ß aggregation for the potential treatment of Alzheimer's disease.

Development of an efficient therapeutic agent for Alzheimer's disease: design and synthesis of dual inhibitors of acetylcholinesterase and serotonin transporter.

To date, acetylcholinesterase (AChE) inhibitors have been clinically effective drugs for the palliative treatment of Alzheimer's disease, but their clinical efficacy is limited, mainly due to their adverse effects on peripheral organs. Since patients of Alzheimer's disease often exhibit depression as well as memory impairment, dual inhibitors of AChE and serotonin transporter (SERT) would be a better therapeutic method. Anti-depressive effects based on SERT inhibition would reduce the dose-related side effects of AChE inhibitors. Such dual inhibitors were designed by the hybridization of rivastigmine and fluoxetine based on a hypothetical model of the AChE active site. Various derivatives were synthesized and evaluated for their in vitro inhibition, and then (S)-5j (RS-1259), which possessed balanced inhibitory activities of AChE (IC(50)=101 nM) and SERT (IC(50)=42 nM), was successfully obtained. An ex vivo experiment in mice indicated that (S)-5j (RS-1259) simultaneously inhibited AChE and SERT in the brain following an oral administration. The simultaneous elevation of extracellular levels of acetylcholine and serotonin in the rat hippocampus was actually confirmed by microdialysis.

Total Synthesis of (±)-Marsupellins A and B via Acetoxymarsupellone Using an Intramolecular Reductive Cyclization of Epoxycyanohydrin Derivative with Cp2TiI.

The first total synthesis of C3- and C9-oxidized ent-longipinane-type sesquiterpenoids containing acetoxymarsupellone, marsupellins A and B, has been accomplished. This unique core common to C3- and C9-oxidized ent-longipinane-type sesquiterpenoids was constructed via a new intramolecular reductive cyclization reaction of an epoxycyanohydrin derivative using Cp2TiI.

Total Synthesis of Pleofugin A, a Potent Inositol Phosphorylceramide Synthase Inhibitor.

X-ray analysis and total synthesis of 1 unambiguously confirmed pleofingin A's absolute configuration. The total synthesis was achieved by convergent assembly of three fragments (12, 14, and 18). This synthetic approach provides access to derivatives of 1 to search for antifungal agents that will be more effective in clinical use.

Synthesis of Methylenebicyclo[3.2.1]octanol by a Sm(II)-Induced 1,2-Rearrangement Reaction with Ring Expansion of Methylenebicyclo[4.2.0]octanone.

Direct conversion of methylenebicyclo[4.2.0]octanone to methylenebicyclo[3.2.1]octanol by a Sm(II)-induced 1,2-rearrangement with ring expansion of the methylenecyclobutane is described. Three conditions were optimized to allow the adaptation of this approach to various substrates. A rearrangement mechanism is proposed involving the generation of a ketyl radical and cyclopentanation by ketyl-olefin cyclization, followed by radical fragmentation and subsequent protonation.

Total Synthesis of (-)-L-755,807: Establishment of Relative and Absolute Configurations.

The first total synthesis of (-)-L-755,807 and its three stereoisomers was achieved by our Horner-Wadsworth-Emmons reaction for stereoselective formation of trisubstituted olefins, highly diastereoselective Darzens condensation to construct the epoxy-γ-lactam ring, and late-stage coupling of the ring and side-chain segments for efficient convergent synthesis. This synthesis shows that the originally proposed structure of natural (-)-L-755,807 was incorrect and establishes its relative and absolute configurations.

A novel beta-sheet breaker, RS-0406, reverses amyloid beta-induced cytotoxicity and impairment of long-term potentiation in vitro.

Fibril formation of amyloid beta peptide (Abeta) is considered to be responsible for the pathology of Alzheimer's disease (AD). The Abeta fibril is formed by a protein misfolding process in which intermolecular beta-sheet interactions become stabilized abnormally. Thus, to develop potential anti-AD drugs, we screened an in-house library to find compounds which have a profile as a beta-sheet breaker. We searched for a beta-sheet breaker profile 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 microg ml(-1)) was found to be capable of significantly inhibiting 25 microM Abeta(1-42) fibrillogenesis and, furthermore, disassembling preformed Abeta(1-42) fibrils in vitro. 3 We then investigated the effect of RS-0406 on 111 nM Abeta(1-42)-induced cytotoxicity in primary hippocampal neurons, and found that 0.3-3 microg ml(-1) RS-0406 ameliorates the cytotoxicity. Moreover, 3 microg ml(-1) RS-0406 reversed 1 micro M Abeta(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 Abeta(1-42) fibrillogenesis, and to protect neurons against Abeta(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.

Total synthesis of (+)-benzastatin E via diastereoselective Grignard addition to 2-acylindoline.

[reaction: see text] A stereoselective total synthesis of (+)-benzastatin E (1) is described. The synthesis involves a diastereoselective Grignard addition to 2-acylindoline 2, which is derived from commercially available (S)-2-indolinecarboxylic acid (3). The unknown absolute configuration of (+)-1 is determined as (9S,10R).

Design and synthesis of dual inhibitors of acetylcholinesterase and serotonin transporter targeting potential agents for Alzheimer's disease.

Highly efficient acetylcholinesterase (AChE) and serotonin transporter (SERT) dual inhibitors, (S)-4 and (R)-13 were designed and synthesized on the basis of the hypothetical model of AChE active site. Both compounds showed potent inhibitory activities against AChE and SERT. [structure: see text]

A novel compound RS-0466 reverses beta-amyloid-induced cytotoxicity through the Akt signaling pathway in vitro.

beta-Amyloid peptide is the principal protein in the senile plaques of Alzheimer's disease and is considered to be responsible for the pathology of Alzheimer's disease. Several studies have shown that beta-amyloid is cytotoxic, using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) as an indicator of viability in cells. Utilizing the MTT assay, we screened an in-house library to find compounds that suppress beta-amyloid-induced inhibition of MTT reduction. From among the screening hits, we focused on 6-ethyl-N,N'-bis(3-hydroxyphenyl)[1,3,5]triazine-2,4-diamine (named RS-0466), which had been newly synthesized in our laboratory. This compound was found to be capable of significantly inhibiting beta-amyloid-induced cytotoxicity in HeLa cells and of reversing the decrease of phosphorylated Akt induced by beta-amyloid. Furthermore, RS-0466 reversed the beta-amyloid-induced impairment of long-term potentiation in rat hippocampal slices. These results raise the possibility that RS-0466 or its derivatives have potential as a therapeutic agent for Alzheimer's disease patients, and its effect is at least in part mediated by activation of Akt.

Conformational analysis of globomycin with a signal peptidase II inhibitory activity using molecular dynamics simulation.

Globomycin (1), a 19-membered cyclic depsipeptide, exhibited an antibiotic activity against gram-negative bacteria by inhibiting signal peptidase II in the cytoplasmic membrane. Although only one conformation of 1 was observed for the crystal structure, it was revealed by 1H NMR spectroscopic analysis that 1 exists as a mixture of two rotational isomers in solution (CDCl3 and CD3OD). A conformational analysis of 1 was, therefore, performed by high-temperature molecular dynamics simulation in combination with 1H NMR analysis to elucidate the conformations in solution. The relative ratio of the major and minor isomers present, which differs depending on the solvent, was then derived from their relative energy differences obtained in the conformational analysis. The difference in the relative ratios corresponded with that calculated from the 1H NMR analysis. Finally, the predicted conformations in solution were compared with that of the X-ray crystal structure to find local and global differences that characterize these conformations.

Synthesis and antimicrobial activity of novel globomycin analogues.

Globomycin, a signal peptidase II inhibitor, and its derivatives show potent antibacterial activity against Gram-negative bacteria. The synthesis and antimicrobial activity of novel globomycin analogues are reported. One of the analogues showed a more potent activity against Gram-negative bacteria than globomycin and also exhibited antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA).

Structure-activity relationships of globomycin analogues as antibiotics.

Globomycin (1a), a signal peptidase II inhibitor, and its derivatives show potent antibacterial activity against Gram-negative bacteria. The synthesis and antimicrobial activity of novel globomycin analogues are reported. The hydroxyl group in the L-Ser residue was essential for the antimicrobial activity and the length of the alkyl side chain greatly influenced the activity. In addition, derivatives that had a modified cyclic core exhibited weak activity. One of the analogues showed a wider antimicrobial spectrum, effective against not only Gram-negative but also Gram-positive bacteria.

RS-4252 inhibits amyloid beta-induced cytotoxicity in HeLa cells.

Progressive deposition of amyloid beta peptide in the senile plaques is a principal event in the neurodegenerative process of Alzheimer's disease. Several reports have demonstrated that amyloid beta is cytotoxic using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) as an indicator of viability in cells. With the MTT assay, we screened an in-house library to find compounds which suppress amyloid beta-induced inhibition of MTT reduction. We have previously reported that 6-ethyl-N,N'-bis(3-hydroxyphenyl)[1,3,5]triazine-2,4-diamine (named RS-0466), found in an in-house library, was capable of significantly inhibiting amyloid beta-induced cytotoxicity in HeLa cells. From further screening hits, we newly focused on 4-(7-hydroxy-2,2,4-trimethyl-chroman-4-yl)benzene-1,3-diol (named RS-4252), which show comparable potency to RS-0466 to ameliorate amyloid beta-induced cytotoxicity. Furthermore, RS-4252 reversed the decrease in phosphorylated Akt by amyloid beta. These results imply that RS-4252 or one of its derivatives has the potential to be a therapeutic for Alzheimer's disease patients, and that activation of Akt is at least in part involved in the effect.