ABSTRACT
A synthetic route to ecteinascidin 743 has been established via an intramolecular cascade Heck reaction to construct the diazabicyclo[3.3.1]nonane skeleton while controlling the two contiguous stereogenic centers. The strategically formed five-membered ring was oxidatively cleaved to generate a dialdehyde intermediate, from which the B ring of ecteinascidin 743 was constructed.
Subject(s)
Alkanes , Cyclization , Stereoisomerism , TrabectedinABSTRACT
Amyloid formation and the deposition of the amyloid-ß peptide are hallmarks of Alzheimer's disease pathogenesis. Immunotherapies using anti-amyloid-ß antibodies have been highlighted as a promising approach for the prevention and treatment of Alzheimer's disease by enhancing microglial clearance of amyloid-ß peptide. However, the efficiency of antibody delivery into the brain is limited, and therefore an alternative strategy to facilitate the clearance of brain amyloid is needed. We previously developed an artificial photo-oxygenation system using a low molecular weight catalytic compound. The photocatalyst specifically attached oxygen atoms to amyloids upon irradiation with light, and successfully reduced the neurotoxicity of aggregated amyloid-ß via inhibition of amyloid formation. However, the therapeutic effect and mode of actions of the photo-oxygenation system in vivo remained unclear. In this study, we demonstrate that photo-oxygenation facilitates the clearance of aggregated amyloid-ß from the brains of living Alzheimer's disease model mice, and enhances the microglial degradation of amyloid-ß peptide. These results suggest that photo-oxygenation may represent a novel anti-amyloid-ß strategy in Alzheimer's disease, which is compatible with immunotherapy.
Subject(s)
Alzheimer Disease/pathology , Amyloid beta-Peptides/drug effects , Amyloid beta-Peptides/metabolism , Boron Compounds/pharmacology , Brain/drug effects , Animals , Brain/pathology , Disease Models, Animal , Humans , Mice , Microglia/metabolism , Phototherapy/methods , Protein Aggregates/drug effectsABSTRACT
The total synthesis of halicloninâ A was accomplished. Starting from 3,5-dimethoxybenzoic acid, a functionalized cyclohexanone fused to a 17-membered ring was prepared through a Birch reduction/alkylation sequence, ring-closing metathesis, intramolecular cyclopropanation, and stereoselective 1,4-addition of an organocopper reagent to an enone moiety. Reductive C-N bond formation via an N,O-acetal forged the 3-azabicyclo[3.3.1]nonane core. The allyl alcohol moiety was constructed by a sequence involving stereoselective α-selenylation of an aldehyde via an enamine, syn-elimination of a selenoxide, and allylation of the aldehyde with an allylboronate. Formation of the 15-membered ring containing a skipped diene was achieved by ring-closing metathesis, and final transformations led to the synthesis of halicloninâ A.
ABSTRACT
Mersicarpine is an aspidosperma alkaloid isolated from the Kopsia genus of plants. Its intriguing structural features have attracted much attention in synthetic organic chemistry, but no biological activity has been reported. Here, we report the effects of mersicarpine on human leukemia cell line HL60. At concentrations above 30 µm, mersicarpine reversibly arrested cell cycle progression in S-phase. At higher concentrations, it induced not only production of reactive oxygen species, but also apoptosis. Macromolecular synthesis assay revealed that mersicarpine specifically inhibits protein synthesis. These results suggest that mersicarpine is a novel translation inhibitor that induces apoptosis.
Subject(s)
Apoptosis/drug effects , Indole Alkaloids/pharmacology , Protein Biosynthesis/drug effects , S Phase/drug effects , HL-60 Cells , Humans , Reactive Oxygen Species/metabolismABSTRACT
A total synthesis of tetrodotoxin was accomplished. A Diels-Alder reaction between a known enone and a siloxy diene gave a tricyclic product, the steric bias of which was used to construct the remaining stereogenic centers. A nitrogen atom was introduced either by a four-step sequence involving a Curtius rearrangement, or a three-step sequence featuring a newly developed transformation of a terminal alkyne into a nitrile. Introduction of the guanidine moiety followed by the formation of the heterocyclic system by cascade reactions led to tetrodotoxin.
Subject(s)
Tetrodotoxin/chemical synthesis , Alkynes/chemistry , Chemistry Techniques, Synthetic , Guanidine/chemistry , Nitriles/chemistry , Nitrogen/chemistry , Tetrodotoxin/chemistryABSTRACT
An alternative synthetic route toward a key intermediate in the total synthesis of isoschizogamine is described. The Claisen-Johnson rearrangement stereoselectively constructed a quaternary carbon. Trifluoroperacetic acid mediated the Baeyer-Villiger oxidation to form a bicyclic lactone. The Mukaiyama-Matsuo protocol converted the lactone into an α,ß-unsaturated lactone, that was used as the substrate for the rhodium-mediated 1,4-addition of an arylboronic acid.
Subject(s)
Indole Alkaloids/chemical synthesis , Boronic Acids/chemistry , Indole Alkaloids/chemistry , Lactones/chemical synthesis , Lactones/chemistry , Molecular Structure , Rhodium/chemistryABSTRACT
During the course of synthetic studies of the Daphniphyllum alkaloids, an unusual reaction of a rhodium carbenoid was observed. The bicyclic substrate, in which an α-diazo-ß-ketoester moiety was present at the 3-position of a 1,4-diene moiety, was treated with rhodium pivalate to produce an intermediate having diene and ketene moieties. This intermediate underwent an intramolecular [4 + 2] cycloaddition reaction to form a tetracyclic compound.
ABSTRACT
The [7-5-5] tricyclic core of the Daphniphyllum alkaloids was constructed, featuring a Claisen-Ireland rearrangement to install the two contiguous stereogenic centers, E1cB elimination to form the tetrasubstituted C-C double bond, and a 2,3-Wittig rearrangement to construct the quaternary carbon. Ring-closing metathesis and an intramolecular carbonyl ene reaction were employed for construction of the requisite ring system.
Subject(s)
Alkaloids/chemistry , Alkaloids/chemical synthesis , Daphniphyllum/chemistry , Chemistry Techniques, Synthetic , Cyclization , StereoisomerismABSTRACT
A total synthesis of (+)-lysergic acid, which features the C-C bond formation between C10 and C11 via cleavage of an aziridine ring, was accomplished.
Subject(s)
Lysergic Acid/chemical synthesis , Aziridines/chemistry , Ergot Alkaloids/chemistry , Indicators and Reagents , Molecular Structure , StereoisomerismABSTRACT
A total synthesis of huperzine R was accomplished. Intramolecular cycloaddition of a nitrile oxide and reductive cleavage of the resulting isoxazoline induced sequential cleavage of the C-C and C-O bonds to form the characteristic bicyclic lactam core with an enone moiety. Construction of the butenolide moiety from the enone afforded huperzine R.
ABSTRACT
A synthesis of cardiopetaline has been accomplished via a Wagner-Meerwein rearrangement of a diol having the denudatine skeleton. The Wagner-Meerwein rearrangement could be facilitated simply by heating the diol with p-toluenesulfonic acid in pivalic acid, without preactivating the pivotal hydroxy group. This strategy does not require differentiation of several hydroxy groups in the substrate for the Wagner-Meerwein rearrangement and could be applied to the synthesis of more highly oxygenated aconitine-type diterpenoid alkaloids.
ABSTRACT
The total synthesis of huperzine Q was accomplished. The synthesis features the construction of the cis-hydrindane skeleton via a Diels-Alder reaction and a ring contraction reaction of an epoxyketone.
ABSTRACT
The main components of the quorum-sensing system are expected to be favorable targets for drug development to combat various chronic infectious diseases. ComA of Streptococcus is an ATP-binding cassette transporter containing a peptidase domain (PEP), which is essential for the quorum-sensing signal production. Using high-throughput screening, we found a potent small molecule that suppressed the S. mutans quorum-sensing pathway through inhibition of PEP activity. The compound effectively attenuated the biofilm formation and competence development of S. mutans without inhibiting cell growth. The kinetic and structural studies with this molecule and a related compound unexpectedly revealed an allosteric site of PEP. This relatively hydrophobic site is thought to undergo large structural changes during the catalytic process. These compounds inhibit PEP activity by binding to and suppressing the structural changes of this site. These results showed that PEP is a good target for inhibitors of the Streptococcus quorum-sensing system.
Subject(s)
Anti-Bacterial Agents/pharmacology , High-Throughput Screening Assays , Quorum Sensing/drug effects , Signal Transduction/drug effects , Streptococcus/drug effects , Streptococcus/physiology , Anti-Bacterial Agents/chemistry , Humans , Microbial Sensitivity Tests , Models, Molecular , Molecular Conformation , Protein Binding , Structure-Activity RelationshipABSTRACT
Aurachinsâ A and B are alkaloids having 3-hydroxyquinoline N-oxide cores. An efficient method for the synthesis of 3-hydroxyquinoline N-oxides was established and is amenable to the total syntheses of aurachinsâ A and B. Alkylation of 1-(2-nitrophenyl)butan-2-one with farnesyl bromide took place selectively at the benzylic position, and subsequent treatment of the alkylated product with sodium tert-butoxide in dimethyl sulfoxide gave aurachinâ B. Alkylation of 1-(2-nitrophenyl)butan-2-one with an epoxy iodide derived from farnesol was used to access aurachinâ A.
Subject(s)
Stigmatella aurantiaca/metabolism , Alkylation , Bromides/chemistry , Butanones/chemistry , Dimethyl Sulfoxide/chemistry , Quinolines/chemical synthesisABSTRACT
Asymmetric total synthesis of (-)-morphine has been accomplished in 18â steps from commercially available 7-methoxy-2-tetralone. Our synthesis features a simple transformation from a readily prepared chiral intermediate, construction of the E-ring by acid-mediated cyclization, and singlet oxygen-mediated manipulation of the C-ring. Transformation of the final stage involves construction of the morphinan skeleton by means of 1,6-addition of in situ generated secondary amine.
Subject(s)
Morphine/chemical synthesis , Cyclization , Morphine/chemistry , Singlet Oxygen/chemistry , Stereoisomerism , Tetralones/chemistryABSTRACT
The enantioselective total synthesis of (-)-tetrodotoxin [(-)-TTX] and 4,9-anhydrotetrodotoxin, which are selective blockers of voltage-gated sodium channels, was accomplished from the commercially available p-benzoquinone. This synthesis was based on efficient stereocontrol of the six contiguous stereogenic centers on the core cyclohexane ring through Ogasawara's method, [3,3]-sigmatropic rearrangement of an allylic cyanate, and intramolecular 1,3-dipolar cycloaddition of a nitrile oxide. Our synthetic route was applied to the synthesis of the tetrodotoxin congeners 11-norTTX-6(R)-ol and 4,9-anhydro-11-norTTX-6(R)-ol through late-stage modification of the common intermediate. Neutral deprotection at the final step enabled easy purification of tetrodotoxin and 11-norTTX-6(R)-ol without competing dehydration to their 4,9-anhydro forms.
Subject(s)
Sodium Channel Blockers/chemical synthesis , Tetrodotoxin/analogs & derivatives , Tetrodotoxin/chemical synthesis , Benzoquinones/chemical synthesis , Benzoquinones/chemistry , Chemistry Techniques, Synthetic , Sodium Channel Blockers/chemistry , Stereoisomerism , Tetrodotoxin/chemistryABSTRACT
Optically pure hinckdentine A was synthesized on a 300 mg scale via an asymmetric catalysis-based strategy. The key steps to the first asymmetric synthesis involved (i) enantioselective dearomative cyclization of an achiral N-acyl indole that allowed for the efficient construction of the key polycyclic indoline intermediate with a crucial tetrasubstituted stereogenic carbon center, (ii) Beckmann fragmentation-mediated ring expansion, (iii) rearrangement-based introduction of an anilinic nitrogen atom, (iv) regioselective tribromination, and (v) final closure of the cyclic amidine moiety.
Subject(s)
Quinazolines/chemistry , Catalysis , Cyclization , Lactams/chemistry , Molecular Structure , Palladium/chemistry , StereoisomerismABSTRACT
Chemical transformation of an early intermediate in our synthesis of huperzine A provided a diverse array of molecules in which a variety of functional groups could be embedded.
Subject(s)
Alkaloids/chemical synthesis , Sesquiterpenes/chemical synthesis , Alkaloids/chemistry , Molecular Structure , Sesquiterpenes/chemistryABSTRACT
The systematic arrangement of a two-carbon unit, hydrogen atom, and oxygen atom on the versatile enal moiety of a non-natural synthetic intermediate successfully led to the unified access to the gelsedine-type alkaloids. The development and use of this new synthetic hub and an array of site-selective transformations resulted in the asymmetric synthesis of (-)-gelsenicine, (-)-gelsedine, (-)-gelsedilam, (-)-14-hydroxygelsenicine, and (-)-14,15-dihydroxygelsenicine.
ABSTRACT
Conversion of readily available vindoline to 11-mesyloxytabersonine, a versatile synthetic intermediate for indole alkaloids, has been achieved by a 9-step sequence in 39% overall yield.