ABSTRACT
The convergent synthesis of the dansyl-labeled probe of the thiophene-3-carboxamide analogue of annonaceous acetogenins, which shows potent antitumor activity, was accomplished by two asymmetric alkynylations of the 2,5-diformyl THF equivalent with an alkyne having a thiophene moiety and another alkyne tagged with a dansyl group. The growth inhibitory profiles toward 39 human cancer cell lines revealed that the probe retained the biological function of its mother compound, and would be useful for studying cellular activity.
Subject(s)
Acetogenins/chemistry , Acetogenins/pharmacology , Antineoplastic Agents/pharmacology , Dansyl Compounds/chemistry , Thiophenes/chemistry , Acetogenins/chemical synthesis , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Molecular Structure , Structure-Activity RelationshipABSTRACT
Five novel acetogenin analogues with a furan, thiophene, or thiazole ring were synthesized, and their inhibitory activities toward human cancer cell lines were evaluated. The analogues showed more potent activities than natural acetogenin. One of them, the thiophene-3-carboxamide analogue, strongly inhibited the growth of human lung cancer cell line NCI-H23 in the xenograft mouse assay without critical toxicity.
Subject(s)
Acetogenins/pharmacology , Amides/pharmacology , Antineoplastic Agents/pharmacology , Neoplasms, Experimental/drug therapy , Thiophenes/pharmacology , Acetogenins/chemical synthesis , Acetogenins/chemistry , Amides/administration & dosage , Amides/chemistry , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Female , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Molecular Structure , Neoplasms, Experimental/pathology , Structure-Activity Relationship , Thiophenes/administration & dosage , Thiophenes/chemistryABSTRACT
Five novel hybrid molecules of annonaceous acetogenins and insecticides targeting mitochondrial complex I were synthesized and their growth inhibitory activities against 39 human cancer cell lines were investigated. It was revealed that the connecting group between the N-methylpyrazole part and the hydrophobic alkyl chain bearing the THF ring influenced their biological activities significantly. Amide-connected analog 2, in particular, showed selective and very potent activity (<10 nM) against some cancer cell lines.
Subject(s)
Acetogenins/chemistry , Acetogenins/pharmacology , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/pharmacology , Cell Proliferation/drug effects , Antineoplastic Agents, Phytogenic/chemical synthesis , Cell Line, Tumor , Drug Screening Assays, Antitumor , HCT116 Cells , HT29 Cells , Humans , Hydrophobic and Hydrophilic Interactions , MCF-7 Cells , Models, Chemical , Molecular Structure , Structure-Activity RelationshipABSTRACT
A 2 : 1 mixture of NCS and Ph(3)P successfully promoted the anti-dichlorination of olefins to provide corresponding dichlorides, serving as a molecular chlorine surrogate generated in situ.
Subject(s)
Alkenes/chemistry , Hydrocarbons, Chlorinated/chemical synthesis , Organophosphates/chemistry , Thiocyanates/chemistry , Hydrocarbons, Chlorinated/chemistry , Molecular StructureABSTRACT
C34-epi and C34-epi-C35-trifluoro analogues of solamin, a mono-THF annonaceous acetogenin, were synthesized. Their inhibitory activity, along with previously synthesized analogues (C35-fluoro, C35-difluoro, and C35-trifluorosolamins), against bovine mitochondrial NADH-ubiquinone oxidoreductase (complex I) was determined. The present study revealed that the methyl group on the γ-lactone moiety is critical to the potent inhibition of complex I by natural acetogenins.
Subject(s)
Acetogenins/chemistry , Acetogenins/pharmacology , Electron Transport Complex I/antagonists & inhibitors , Lactones/chemistry , Lactones/pharmacology , Mitochondria/drug effects , Mitochondria/enzymology , Animals , Cattle , Humans , Models, Molecular , Structure-Activity RelationshipABSTRACT
A stereoconvergent access to chiral carbocyclic building blocks is reported. 6-(3'-Hydroxy-4'-methylpent-4'-enyl)-3-methoxy cyclohex-2-enone () that consists of four stereoisomers, i.e., racemic ca. 1 : 1 diastereomers, is converted to enantiomerically pure carbocycles through a combination of regioselective catalytic asymmetric reduction and alkylative remote stereoinduction. The present stereoconvergent strategy has allowed the formal synthesis of bioactive (-)-dysidiolide.
Subject(s)
4-Butyrolactone/analogs & derivatives , Cyclohexenes/chemistry , 4-Butyrolactone/chemical synthesis , 4-Butyrolactone/chemistry , Molecular Structure , StereoisomerismABSTRACT
Palladium-catalyzed cascade C-H alkenylation and arylation provides convenient access to polycyclic aromatic compounds. Treatment of 3-bromoaniline derivatives bearing a bromocinnamyl group on the nitrogen atom with a catalytic amount of [Pd(OAc)(2)] and PCy(3)·HBF(4) in the presence of Cs(2)CO(3) in dioxane affords naphthalene-fused indole derivatives in good yields. This double cyclization reaction is also applicable to heterocyclic substrates, giving fused indoles containing a heteroaromatic ring such as dibenzofuran, dibenzothiophene, carbazole, indole, or benzofuran through heterocyclic C-H arylation. When using a 2,6-unsubstituted aniline derivative, the first C-H arylation preferentially proceeds at the more hindered position of the aniline ring.
Subject(s)
Benzofurans/chemistry , Palladium/chemistry , Polycyclic Compounds/chemistry , Polycyclic Compounds/chemical synthesis , Alkylation , Catalysis , Cyclization , Hydrogen BondingABSTRACT
Allyl N-tosyloxycarbamates are found to be catalytically transformed into ß-brominated oxazolidinones with FeBr(2)/n-Bu(4)NBr in t-BuOH.
Subject(s)
Carbamates/chemistry , Iron/chemistry , Amination , Catalysis , Halogenation , Molecular StructureABSTRACT
The alkylation of dienolates generated from 3-methoxycycloalk-2-enones having a 3'-hydroxyl alkenyl chain provides the corresponding quaternized cycloalkenones in a highly diastereoselective manner. The high degree of stereocontrol in the α-quaternization possibly implies intervention of a rigid chelating transition state that allows an efficient 1,4-asymmetric induction to take place.
Subject(s)
Chemistry Techniques, Synthetic/methods , Hydrocarbons, Alicyclic/chemistry , Alkylation , Hydrocarbons, Alicyclic/chemical synthesis , Molecular Structure , StereoisomerismABSTRACT
The convergent synthesis of C35-fluorinated analogues of solamin, a mono-THF Annonaceous acetogenin, has been achieved by the Sonogashira coupling of the THF ring fragment and the fluorinated γ-lactone fragment. It was revealed that the number of fluorine atoms on the γ-lactone moiety affects the growth inhibitory activities against human cancer cell lines.
Subject(s)
Acetogenins/chemical synthesis , Acetogenins/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Drug Design , Growth Inhibitors/chemical synthesis , Growth Inhibitors/pharmacology , Acetogenins/chemistry , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Female , Growth Inhibitors/chemistry , Halogenation , Humans , Male , Neoplasms/drug therapyABSTRACT
A novel route to (±)-platencin is reported, in which the highly stereoselective alkylative quaternization of a cyclohexenone scaffold via 1,4-diastereoinduction and two radical carbon-carbon bond-forming reactions that involve titanium(III)-mediated cyclization and stannyl-radical-mediated skeletal rearrangement are utilized.
Subject(s)
Aminophenols/chemical synthesis , Anti-Bacterial Agents/chemical synthesis , Polycyclic Compounds/chemical synthesis , Aminophenols/chemistry , Anti-Bacterial Agents/chemistry , Cyclization , Molecular Structure , Polycyclic Compounds/chemistry , StereoisomerismABSTRACT
The asymmetric alkynylation of aliphatic and aromatic aldehydes with propiolates was mediated by dialkylzinc and a novel prolinol catalyst without high reagent loading and any additives, such as Ti(Oi-Pr)(4), to give the corresponding γ-hydroxy-α,ß-acetylenic esters with high enantiomeric excess of up to 95%.
Subject(s)
Aldehydes/chemistry , Alkynes/chemical synthesis , Chemistry, Organic , Esters/chemical synthesis , Propionates/chemistry , Pyrrolidines/chemistry , Alkynes/chemistry , Catalysis/drug effects , Chromatography, High Pressure Liquid , Magnetic Resonance Spectroscopy , Molecular Structure , Organometallic Compounds/chemistry , Solutions , Stereoisomerism , Zinc Compounds/chemistryABSTRACT
A novel photochemical C-H carbamoylation of an octahydroisoindole derivative with PhNCO has allowed the authors to provide a unique access to a highly functionalized proline motif from which total synthesis of (±)-kainic acid, a bioactive marine alkaloid, has been accomplished.
Subject(s)
Indole Alkaloids/chemical synthesis , Kainic Acid/analogs & derivatives , Kainic Acid/chemical synthesis , Indole Alkaloids/chemistry , Kainic Acid/chemistry , Marine Biology , Molecular Structure , StereoisomerismABSTRACT
A convergent asymmetric total synthesis of (+)-danicalipin A is accomplished, in which two chlorinated fragments are stereoselectively joined by 1,3-dipolar coupling, leading to the confirmation of the absolute configuration of the natural product.
Subject(s)
Lipids/chemical synthesis , Lipids/chemistry , Molecular Structure , Ochromonas/chemistry , StereoisomerismABSTRACT
The convergent synthesis of fluorescence-labeled solamin, an antitumor Annonaceous acetogenin, was accomplished by two asymmetric alkynylations of 2,5-diformyl tetrahydrofuran with an alkyne tagged with fluorescent groups and another alkyne with an α,ß-unsaturated γ-lactone. Assay for the growth inhibitory activity against human cancer cell lines revealed that the probe with the fluorescent groups at the end of the hydrocarbon chain may have the same mode of action as natural acetogenins. The merged fluorescence of dansyl-labeled solamin and MitoTracker Red suggests that Annonaceous acetogenins localize in the mitochondria.
Subject(s)
Acetogenins/chemical synthesis , Fluorescent Dyes/chemical synthesis , Acetogenins/pharmacokinetics , Antineoplastic Agents/chemical synthesis , Benzethonium , Cell Line, Tumor , Cell Proliferation/drug effects , Fluorescent Dyes/pharmacokinetics , Humans , Mitochondria/metabolism , Tissue DistributionABSTRACT
The palladium(0)-catalyzed direct construction of bicyclic heterocycles is described. Treatment of propargyl bromides that have nucleophilic functional groups connected by two or three carbon atoms with catalytic [Pd(PPh(3))(4)] affords bis-cyclization products in good yields. The desired bicyclic heterocycles can be obtained selectively when using substrates with appropriate nucleophilic groups. We also describe the reaction of a 2-alkynylazetidine derivative with a catalytic amount of [Pd(PPh(3))(4)] under base-free conditions, which affords the same fused heterocycles as the corresponding propargyl bromides.
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Nitrogen/chemistry , Palladium/chemistry , Pargyline/analogs & derivatives , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Catalysis , Cyclization , Molecular Structure , Pargyline/chemistryABSTRACT
The enantioselective total synthesis of (+)-hexachlorosulfolipid, a cytotoxin found in the Adriatic mussel Mytilus galloprovincialis, is described. The unique chlorinated hydrocarbon motif of the lipid is successfully furnished by a series of dichlorination reactions of chiral epoxides with chlorophosphonium reagent generated in situ from Ph(3)P/NCS. The present total synthesis has allowed the confirmation of the absolute configuration of the natural cytotoxic (+)-hexachlorosulfolipid originally proposed by Fattorusso, Ciminiello, and co-workers.
Subject(s)
Lipids/chemical synthesis , Mytilus/chemistry , Animals , Computer Simulation , Lipids/chemistry , Lipids/isolation & purification , Molecular Conformation , StereoisomerismABSTRACT
A novel palladium(0)-catalyzed domino cyclization of 2-alkynylaziridines with isocyanates through ring expansion is described. Treatment of N-protected 2-(4-aminobut-1-ynyl)aziridine derivatives with a catalytic amount of Pd(PPh(3))(4) and aryl isocyanates in THF at room temperature affords 4-(4,5-dihydropyrrol-2-yl)imidazolidin-2-one derivatives in good yields. Interestingly, bis-adducts were selectively obtained by use of excess isocyanate (5 equiv) at lower reaction temperature.
Subject(s)
Aziridines/chemistry , Aziridines/chemical synthesis , Heterocyclic Compounds/chemistry , Isocyanates/chemistry , Organometallic Compounds/chemistry , Palladium/chemistry , Catalysis , Cyclization , Molecular Structure , StereoisomerismABSTRACT
Most Annonaceous acetogenins are characterized by between one and three THF ring(s) with one or two flanking hydroxyl group(s) in the center of a C32/34 fatty acid, and the terminal carboxylic acid is combined with a 2-propanol unit to form an alpha,beta-unsaturated gamma-lactone. While many studies have addressed the properties and synthesis of natural acetogenins due to their attractive biological activities and unique structural features, a number of analogues have also been described. This review covers the design, synthesis, and biological evaluation of acetogenin analogues.
Subject(s)
Acetogenins/chemical synthesis , Acetogenins/pharmacology , Drug Design , Acetogenins/chemistry , Animals , Chemistry, Pharmaceutical , Furans/chemistry , Humans , Hydrocarbons/chemistry , Lactones/chemistryABSTRACT
The second-generation approach to (-)-agelastatin A has been established. The present strategy features the FeBr(2)-mediated radical cyclization of 2-cyclopentenyloxycarbonyl azide that allows for the stereoselective installation of a cis-vicinal aminobromo functionality suitable for producing the BCD-ring system of agelastatin A. The aminobromination method streamlines access to oxazolidinone, a key intermediate in the previously reported synthesis, thereby culminating in the new total synthesis of (-)-agelastatin A.