ABSTRACT
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.
ABSTRACT
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.
Subject(s)
Lactams/chemical synthesis , Pyrones/chemical synthesis , Lactams/chemistry , Models, Molecular , Molecular Structure , Pyrones/chemistry , StereoisomerismABSTRACT
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.
ABSTRACT
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.
Subject(s)
Antifungal Agents/chemical synthesis , Depsipeptides/chemical synthesis , Glycosphingolipids/chemistry , Hexosyltransferases/antagonists & inhibitors , Crystallization , Cyclization , Inhibitory Concentration 50 , Molecular Structure , Saccharomyces cerevisiae/drug effects , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Asteraceae/chemistry , Biological Products/chemical synthesis , Oxygen/chemistry , Sesquiterpenes/chemical synthesis , Biological Products/chemistry , Catalysis , Molecular Conformation , Sesquiterpenes/chemistry , Stereoisomerism , Vanadium/chemistryABSTRACT
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.
ABSTRACT
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.
Subject(s)
Alkenes/chemistry , Epoxy Compounds/chemical synthesis , Lactams/chemical synthesis , Epoxy Compounds/chemistry , Lactams/chemistry , Molecular Structure , StereoisomerismABSTRACT
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.
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Hydroxylation , Molecular Structure , StereoisomerismABSTRACT
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.
Subject(s)
Acrylates/chemical synthesis , Phosphonoacetic Acid/analogs & derivatives , Phosphonoacetic Acid/chemical synthesis , Acrylates/chemistry , Halogenation , Phosphonoacetic Acid/chemistry , StereoisomerismABSTRACT
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.
Subject(s)
Alzheimer Disease/drug therapy , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/therapeutic use , Drug Design , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Selective Serotonin Reuptake Inhibitors/therapeutic use , Serotonin Plasma Membrane Transport Proteins/metabolism , Acetylcholinesterase/metabolism , Alzheimer Disease/enzymology , Animals , Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/pharmacology , Humans , Selective Serotonin Reuptake Inhibitors/chemistry , Selective Serotonin Reuptake Inhibitors/pharmacologyABSTRACT
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.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Peptides/chemistry , Biochemistry/methods , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Magnetic Resonance Spectroscopy , Microbial Sensitivity Tests , Peptides/pharmacology , Structure-Activity RelationshipABSTRACT
Amyloid beta peptide in the senile plaques of patients with Alzheimer's disease is considered to be responsible for the pathology of Alzheimer's disease. We have previously reported that 6-ethyl-N,N'-bis(3-hydroxyphenyl)[1,3,5]triazine-2,4-diamine, RS-0466, is capable of significantly inhibiting amyloid beta-induced cytotoxicity in HeLa cells. To determine various profiles of RS-0466, we investigated whether RS-0466 would enhance the neuroprotective effect of brain-derived neurotrophic factor on amyloid beta(1-42)-induced cytotoxicity in rat cortical neurones. Consistent with previous observations, brain-derived neurotrophic factor ameliorated amyloid beta(1-42)-induced cytotoxicity. Furthermore, co-application of RS-0466 enhanced the neuroprotective effect of brain-derived neurotrophic factor. RS-0466 also reversed amyloid beta(1-42)-induced decrease of brain-derived neurotrophic factor-triggered phosphorylated Akt. These results raise the possibility that RS-0466 or one of its derivatives has potential to enhance the neuroprotective effect of brain-derived neurotrophic factor, and could serve as a therapeutic agent for patients with Alzheimer's disease.
Subject(s)
Amyloid beta-Peptides/antagonists & inhibitors , Cerebral Cortex/drug effects , Microtubule-Associated Proteins/drug effects , Neuroprotective Agents/therapeutic use , Peptide Fragments/antagonists & inhibitors , Triazines/therapeutic use , Amyloid beta-Peptides/toxicity , Animals , Cells, Cultured , Cerebral Cortex/metabolism , Peptide Fragments/toxicity , Rats , Rats, Sprague-DawleyABSTRACT
Alzheimer's disease (AD) has been treated with acetylcholinesterase (AChE) inhibitors such as donepezil. However, the clinical usefulness of AChE inhibitors is limited mainly due to their adverse peripheral effects. Depression seen in AD patients has been treated with serotonin transporter (SERT) inhibitors. We considered that combining SERT and AChE inhibition could improve the clinical usefulness of AChE inhibitors. In a previous paper, we found a potential dual inhibitor, 1, of AChE (IC50=101 nM) and SERT (IC50=42 nM), but its AChE inhibition activity was less than donepezil (IC50=10 nM). Here, we report the conformationally restricted (R)-18a considerably enhanced inhibitory activity against AChE (IC50=14 nM) and SERT (IC50=6 nM).
Subject(s)
Carrier Proteins/antagonists & inhibitors , Cholinesterase Inhibitors/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Membrane Glycoproteins/antagonists & inhibitors , Membrane Transport Proteins , Nerve Tissue Proteins , Alzheimer Disease/drug therapy , Animals , Cholinesterase Inhibitors/pharmacology , Drug Design , Enzyme Inhibitors/pharmacology , Inhibitory Concentration 50 , Magnetic Resonance Spectroscopy , Mice , Molecular Conformation , Rats , Serotonin Plasma Membrane Transport Proteins , Structure-Activity RelationshipABSTRACT
A dual inhibitor of acetylcholinesterase (AChE) and serotonin transporter (SERT), RS-1259 (4-[1S)-methylamino-3-(4-nitrophenoxy)]propylphenyl N,N-dimethylcarbamate (fumaric acid)(1/2)salt), was newly synthesized. RS-1259 simultaneously inhibited AChE and SERT in the brain following an oral administration in mice and rats. Actual simultaneous elevation of extracellular levels of 5-HT and ACh in the rat hippocampus was confirmed by microdialysis. The compound was as effective as SERT inhibitors such as fluoxetine and fluvoxamine in a 5-hydroxytryptophan-enhancing test in mice. Spatial memory deficits in the two-platform task of a water maze in aged rats were ameliorated by RS-1259 as well as donepezil. Both RS-1259 and donepezil increased the awake episodes in the daytime electroencephalogram of rats. Although RS-1259 was weaker than donepezil in enhancing central cholinergic transmission, as observed by ACh elevation in the hippocampus and memory enhancement in aged rats, the efficacy of RS-1259 on the consciousness level, which reflects the whole activity in the brain, was almost the same as that of donepezil. These results suggest that both cholinergic and serotonergic systems are involved in maintaining brain arousal and that a dual inhibitor of AChE and SERT may be useful for the treatment of cognitive disorders associated with reduced brain activity such as in Alzheimer's disease.
Subject(s)
Alzheimer Disease/drug therapy , Carbamates/pharmacology , Carbamates/therapeutic use , Carrier Proteins/antagonists & inhibitors , Cholinesterase Inhibitors/pharmacology , Cholinesterase Inhibitors/therapeutic use , Fumarates/pharmacology , Fumarates/therapeutic use , Membrane Glycoproteins/antagonists & inhibitors , Membrane Transport Proteins , Nerve Tissue Proteins/antagonists & inhibitors , Acetylcholinesterase/metabolism , Administration, Oral , Aging/drug effects , Aging/physiology , Alzheimer Disease/metabolism , Animals , Carbamates/chemistry , Carrier Proteins/physiology , Cholinesterase Inhibitors/chemistry , Fumarates/chemistry , Hippocampus/drug effects , Hippocampus/enzymology , Hippocampus/metabolism , Male , Maze Learning/drug effects , Maze Learning/physiology , Membrane Glycoproteins/physiology , Memory/drug effects , Memory/physiology , Mice , Microdialysis , Motor Activity/drug effects , Motor Activity/physiology , Nerve Tissue Proteins/physiology , Rats , Rats, Inbred F344 , Rats, Sprague-Dawley , Rats, Wistar , Serotonin Plasma Membrane Transport ProteinsABSTRACT
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.
Subject(s)
Amyloid beta-Peptides/antagonists & inhibitors , Chromans/pharmacology , Phenols/pharmacology , Protein Serine-Threonine Kinases , Amyloid beta-Peptides/toxicity , HeLa Cells , Humans , Oxidation-Reduction , Peptide Fragments/toxicity , Phosphorylation , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins c-akt , Tetrazolium Salts/analysis , Thiazoles/analysis , Triazines/pharmacologyABSTRACT
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).
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Peptides/chemical synthesis , Peptides/pharmacology , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Indicators and Reagents , Microbial Sensitivity Tests , Staphylococcus aureus/drug effects , Structure-Activity RelationshipABSTRACT
We have designed and synthesized a dual inhibitor of acetylcholinesterase (AChE) and serotonin transporter (SERT) as a novel class of treatment drugs for Alzheimer's disease on the basis of a hypothetical model of the AChE active site. Dual inhibitions of AChE and SERT would bring about greater therapeutic effects than AChE inhibition alone and avoid adverse peripheral effects caused by excessive AChE inhibition. Compound (S)-6j exhibited potent inhibitory activities against AChE (IC(50)=101 nM) and SERT (IC(50)=42 nM). Furthermore, (S)-6j showed inhibitory activities of both AChE and SERT in mice brain following oral administration.
Subject(s)
Acetylcholinesterase/metabolism , Alzheimer Disease/drug therapy , Carrier Proteins/antagonists & inhibitors , Cholinesterase Inhibitors/chemical synthesis , Drug Design , Membrane Glycoproteins/antagonists & inhibitors , Membrane Transport Proteins , Nerve Tissue Proteins , Alzheimer Disease/metabolism , Animals , Carrier Proteins/metabolism , Cholinesterase Inhibitors/pharmacology , Cholinesterase Inhibitors/therapeutic use , Dose-Response Relationship, Drug , Membrane Glycoproteins/metabolism , Mice , Rats , Serotonin Plasma Membrane Transport Proteins , Structure-Activity RelationshipABSTRACT
[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).