RESUMEN
Herein, we report the first protecting group-free total synthesis of (-)-boscartin H, which features a 5-12-5-fused tricyclic structure. The key steps, which include a diastereoselective THF-ring-forming/aldol reaction sequence and ring-closing metathesis, afforded high stereoselectivity with (-)-boscartin H obtained in 3.6% overall yield using a 11-step long linear sequence. In addition, X-ray crystallography clearly confirmed the stereochemistry of boscartin H.
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Herein, we describe the chemoselective one-pot cleavage and oxidation of silyl ethers using catalytic amount of TsOH·H2O and IBX in DMSO. The oxidation of primary alkyl TBS ethers afforded the corresponding aldehydes in 51-94% yields, in the presence of aryl TBS, MOM, and PMB ethers, as well as N-Boc and acetonide groups. Secondary benzyl TBS ethers bearing aryl TBS ethers were also oxidized to ketones in moderate yields. A possible reaction pathway was also proposed.
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This study outlines the total synthesis of (+)-monocillin II, wherein a cis-isomer selectively produces a trans-isomer during the ring-closing metathesis. The Mitsunobu reaction conducted at -60 °C, facilitating the formation of an ester bond, was the key to completing the total synthesis, which was accomplished in the longest linear sequence of 10 steps with an overall yield of 9.3%.
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Cyclic ß-1,2-glucan synthase (CGS) is a key enzyme in production of cyclic ß-1,2-glucans (CßGs) which are involved in bacterial infection or symbiosis to host organisms. Nevertheless, a mechanism of cyclization, the final step in the CGS reaction, has not been fully understood. Here we performed functional and structural analyses of the cyclization domain of CGS alone from Thermoanaerobacter italicus (TiCGSCy). We first found that ß-glucosidase-resistant compounds are produced by TiCGSCy with linear ß-1,2-glucans as substrates. The 1H-NMR analysis revealed that these products are CßGs. Next, action pattern analyses using ß-1,2-glucooligosaccharides revealed a unique reaction pattern: exclusive transglycosylation without hydrolysis and a hexasaccharide being the minimum length of the substrate. These analyses also showed that longer substrate ß-1,2-glucooligosaccharides are preferred, being consistent with the fact that CGSs generally produce CßGs with degrees of polymerization of around 20. Finally, the overall structure of the cyclization domain of TiCGSCy was found to be similar to those of ß-1,2-glucanases in phylogenetically different groups. Meanwhile, the identified catalytic residues indicated clear differences in the reaction pathways between these enzymes. Overall, we propose a novel reaction mechanism of TiCGSCy. Thus, the present group of CGSs defines a new glycoside hydrolase family, GH189. KEY POINTS: ⢠It was clearly evidenced that cyclization domain alone produces cyclic ß-1,2-glucans. ⢠The domain exclusively catalyzes transglycosylation without hydrolysis. ⢠The present catalytic domain defines as a new glycoside hydrolase family 189.
Asunto(s)
Glucanos , Glicósido Hidrolasas , beta-Glucanos , Ciclización , CatálisisRESUMEN
Juglorubin is a natural dye isolated from the culture of Streptomyces sp. 3094, 815, and GW4184. It has been previously synthesized via the biomimetic dimerization of juglomycin C, a plausible genetic precursor. In this study, the derivatives of juglorubin, 1-O-acetyljuglorubin dimethyl ester and juglorubin dimethyl ester, were found to exhibit antiviral activity against hepatitis C virus (HCV) without exerting any remarkable cytotoxicity against host Huh-7 cells. They also inhibited liver X receptor α activation and lipid droplet accumulation in Huh-7 cells. These findings suggest that 1-O-acetyljuglorubin dimethyl ester and juglorubin dimethyl ester targeted the host factors required for HCV production.
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Hepacivirus , Hepatitis C , Humanos , Hepacivirus/genética , Línea Celular , Ésteres , Replicación Viral , Antivirales/farmacologíaRESUMEN
In this study, we report the total syntheses of Ganoderma-derived meroterpenoids, (-)-oregonensin A, (-)-chizhine E, (-)-applanatumol U, and (-)-ent-fornicin A. The 3-alkyl-5-aryl-γ-butenolide skeleton, a common motif of these meroterpenoids, was constructed through the enantioselective reductive lactonization of the γ-keto ester, alkylation, and sulfoxide-ß-syn-elimination. This flexible approach enabled enantioselective access to these meroterpenoids with the longest linear sequence of 6-8 steps, and in 21-36% overall yield, respectively.
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Ganoderma , Estructura Molecular , Terpenos , FuranosRESUMEN
The first total synthesis of corallocin A is described herein. The Suzuki coupling reaction as a key step proceeded with high stereoselectivity and in good yield. Robust transformations, including Vilsmeier-Haack formylation and Wittig reaction, allowed for effective access to corallocin A.
RESUMEN
Herein, we describe the first total synthesis of cochlearolâ B, a meroterpenoid natural product featuring a 4/5/6/6/6-fused pentacyclic structure. Key steps, oxidative cyclization and subsequent intramolecular [2+2] photocycloaddition, which constructed the pentacyclic structure in highly stereoselective manner, allowed efficient access to cochlearolâ B with the longest linear sequence of 16 steps, and in 9 % overall yield. Single-crystal X-ray crystallographic analysis clearly confirmed the stereochemistry of cochlearolâ B.
Asunto(s)
Luz , Terpenos/síntesis química , Productos Biológicos/síntesis química , Productos Biológicos/química , Cristalografía por Rayos X , Reacción de Cicloadición , Conformación Molecular , Oxidación-Reducción , Estereoisomerismo , Terpenos/químicaRESUMEN
4'-Ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) and 4'-ethynyl-2'-deoxyadenosine (EdA) are nucleoside analogues which inhibit human immunodeficiency virus type 1 (HIV-1) reverse transcriptase. EdAP, a cyclosaligenyl (cycloSal) phosphate derivative of EdA, inhibits the replication of the influenza A virus. The common structural feature of these compounds is the ethynyl group at the 4'-position. In this study, these nucleoside analogues were prepared by a common synthetic strategy starting from the known 1,2-di-O-acetyl-D-ribofuranose. Biological evaluation of EdAP revealed that this compound reduced hepatitis B virus (HBV) replication dose-dependently without cytotoxicity against host cells tested in this study.
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Antivirales/síntesis química , Nucleótidos de Desoxiadenina/síntesis química , Desoxiadenosinas/síntesis química , Virus de la Hepatitis B/efectos de los fármacos , Replicación Viral/efectos de los fármacos , Antivirales/farmacología , Línea Celular , Nucleótidos de Desoxiadenina/farmacología , Desoxiadenosinas/farmacología , Virus de la Hepatitis B/fisiología , HumanosRESUMEN
Juglorubin, juglorescein, and juglocombins A/B are naturally occurring naphthoquinone dimers isolated from Streptomyces sp. These dimers are proposed to be biogenetically derived from juglomycin C, a monomeric naphthoquinone isolated from the same Streptomyces sp. In this study, the dimerization of a juglomycin C derivative, a key step in the total syntheses of these natural products, was investigated. Juglorubin was synthesized from the minor product of the dimerization via the formation of the juglocombin A/B stereoisomers. A mechanism for the dimerization reaction as well as a plausible biosynthetic pathway to obtain juglorubin from juglomycin C are proposed. Furthermore, the antibacterial and cytotoxic activities of five synthetic compounds were evaluated. Among the compounds tested in this study, 1'-O-methyljuglocombin B dimethyl ester and juglomycin C exhibited antibacterial activity against Bacillus subtilis. 1'-O-Methyljuglocombin B dimethyl ester and juglomycin C showed cytotoxicity against human colon carcinoma HCT116 cells and human leukemia HL-60 cells. 1'-O-Methyljuglocombin B dimethyl ester exhibited cytotoxicity against human normal MRC-5 cells as strong as that against human cancer cells. In contrast, juglomycin C was less toxic against normal MRC-5 cells, indicating a significant selectivity toward cancer cells.
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Antibacterianos/síntesis química , Antibacterianos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Naftoquinonas/síntesis química , Naftoquinonas/farmacología , Antibacterianos/química , Antineoplásicos/química , Bacillus subtilis/efectos de los fármacos , Línea Celular Tumoral , Técnicas de Química Sintética , Escherichia coli/efectos de los fármacos , Humanos , Naftoquinonas/químicaRESUMEN
The antibacterial and cytotoxic activity of seven racemic lactams and both enantiomers of flavipucine were evaluated. Of the compounds tested in this study, flavipucine and phenylflavipucine displayed bactericidal activity against Bacillus subtilis. These results indicate that the pyridione epoxide moiety is a pharmacophore for antibacterial activity against B. subtilis. Flavipucine showed cytotoxic activity against several cancer cells. The cytotoxic activity of flavipucine against human leukemia HL-60 cells is as strong as that of SN-38, the active metabolite of irinotecan. In contrast, the cytotoxic activity of flavipucine against nonneoplastic HEK293 cells and human normal MRC-5 cells is weaker than that of SN-38. No significant differences in the biological activity of the racemates or enantiomers of flavipucine were observed.
Asunto(s)
Antibacterianos/farmacología , Antineoplásicos/farmacología , Bacillus subtilis/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Antibacterianos/síntesis química , Antibacterianos/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Piridonas/síntesis química , Piridonas/química , Piridonas/farmacología , Relación Estructura-ActividadRESUMEN
Both enantiomers of axially chiral bis(dinaphthofuran) were prepared in only two steps from 1'-hydroxy-4'-methoxy-2,2'-binaphthalenyl-1,4-dione, followed by optical resolution via high-performance liquid chromatography (HPLC) using a chiral stationary phase (CSP). The absolute configurations were determined by comparison of experimental and calculated vibrational circular dichroism (VCD) spectra. Synthetic bis(dinaphthofuran) exhibited a broad and unstructured emission derived from an intramolecular excimer in both solution and solid state. The methylene bridge brings both chromophores close to each other and induces significant changes in the photophysical behavior. Chiral bis(dinaphthofuran) displayed a bathochromic shift in emission, as compared to the racemic mixture in the solid state. Furthermore, the compounds showed high circularly polarized luminescence (CPL) with a dissymmetry factor ( glum) of 10-3 at 405 nm upon excitation at 265 nm in a methanol solution. This compound serves as a model for the design and synthesis of organic materials having CPL activity.
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Total syntheses of juglorescein and juglocombinsâ A and B are reported. The highly oxygenated 6/6/5/6/6-fused pentacyclic ring system of these natural products was constructed through a bioinspired dimerization of 1,4-naphthoquinone. Notably, five new stereogenic centers were constructed in a single step by the dimerization reaction. The epoxide intermediate obtained from the dimerization was successfully converted into juglocombinsâ A and B through photoinduced reduction of the epoxide, dehydration, and conversion of the resultant quinone into a hydroquinone derivative. The same epoxide intermediate was also converted into a dicarboxylic acid, which was transformed into juglorescein through intramolecular lactonization, hydrolysis of the resulting lactone, and removal of the protecting groups. Furthermore, the relative and absolute configurations of juglorescein and juglocombinsâ A and B were determined.
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Herein, we report the total syntheses of (+)-ganocin A and (-)-cochlearol B, featuring pentacyclic skeletons, in optically active forms. We utilized asymmetric Corey-Bakshi-Shibata reduction, phenolic oxidative cyclization, the intramolecular radical cyclization-benzylic oxidative cyclization sequence, and intramolecular [2 + 2] photocycloaddition. These key steps enabled enantioselective access with the longest linear sequence of 17 steps and 9% overall yield for (+)-ganocin A and with 16 steps and 9% overall yield for (-)-cohlearol B.
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In this study, we achieved an eight-step enantioselective synthesis of (-)-lamellodysidine A, a structurally intriguing sesquiterpene natural product featuring a 5/5/6/6-fused tetracyclic skeleton that was obtained from the marine sponge Lamellodysidea herbacea. The key to the synthesis is a cascade reaction that includes an intramolecular Diels-Alder reaction. In addition, single-crystal X-ray crystallographic analysis of the synthetic (-)-lamellodysidine A clearly confirmed the proposed stereochemistry and absolute configuration.
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The Birch reduction dearomatizes arenes into 1,4-cyclohexadienes. Despite substantial efforts devoted to avoiding ammonia and cryogenic conditions, the traditional, cumbersome, and dangerous procedure remains the standard. The Benkeser reduction with lithium in ethylenediamine converts arenes to a mixture of cyclohexenes and cyclohexanes; this is operationally easier than the Birch reduction but does not afford 1,4-cyclohexadienes. Here, we report a Birch reduction promoted by lithium and ethylenediamine (or analogs) in tetrahydrofuran at ambient temperature. Our method is easy to set up, inexpensive, scalable, rapid, accessible to any chemical laboratory, and capable of reducing both electron-rich and electron-deficient substrates. Our protocol is also compatible with organocuprate chemistry for further functionalization.
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In this study, the synthesis of N-alkyl-2-halophenazin-1-ones has been established. Six N-alkyl-2-halophenazin-1-ones, including WS-9659 B and marinocyanins A and B, were synthesized by the direct oxidative condensation of 4-halo-1,2,3-benzenetriol with the corresponding N-alkylbenzene-1,2-diamines. One of the most significant features of the present method is that it can be successfully applied to the synthesis of N-alkyl-2-chlorophenazin-1-ones. The traditional chlorination of N-alkyl-phenazin-1-ones with N-chlorosuccinimide selectively occurs at the 4-position to afford the undesired N-alkyl-4-chlorophenazin-1-ones. Our synthetic route successfully circumvents this problem, culminating in the first chemical synthesis of WS-9659 B. The cytotoxicity of six N-alkyl-2-halophenazin-1-ones and three N-alkylphenazin-1-ones against human promyelocytic leukemia HL-60, human lung cancer A549, and normal MRC-5 cells was evaluated. Among the compounds tested in this study, 2-chloropyocyanin possesses significant selectivity toward A549 cells. The cytotoxic evaluation provides structural insights into the potency and selectivity of these compounds for cancer cells.
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Piperitenone oxide, a major chemical constituent of the essential oil of spearmint, Mentha spicata, induces differentiation in human colon cancer RCM-1 cells. In this study, piperitenone oxide and trans-piperitenone dioxide were prepared as racemic forms by epoxidation of piperitenone. The relative configuration between two epoxides in piperitenone dioxide was determined to be trans by 1H NMR analysis and nuclear Overhauser effect spectroscopy (NOESY) in conjunction with density functional theory (DFT) calculations. Optical resolution of (±)-piperitenone oxide by high-performance liquid chromatography (HPLC) using a chiral stationary phase (CSP) afforded both enantiomers with over 98% enantiomeric excess (ee). Evaluation of the differentiation-inducing activity of the synthetic compounds revealed that the epoxide at C-1 and C-6 in piperitenone oxide is important for the activity, and (+)-piperitenone oxide has stronger activity than (-)-piperitenone oxide. The results obtained in this study provide new information on the application of piperitenone oxide and spearmint for differentiation-inducing therapy. Furthermore, natural piperitenone oxide was isolated from M. spicata. The enantiomeric excess of the isolated natural piperitenone oxide was 66% ee. Epoxidation of piperitenone with hydrogen peroxide proceeded in a phosphate buffer under weak basic conditions to give (±)-piperitenone oxide. These results suggest that the nonenzymatic epoxidation of piperitenone, which causes a decrease in the enantiomeric excess of natural piperitenone oxide, is accompanied by an enzymatic epoxidation in the biosynthesis of piperitenone oxide.
Asunto(s)
Diferenciación Celular/efectos de los fármacos , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/patología , Compuestos Epoxi/aislamiento & purificación , Compuestos Epoxi/farmacología , Mentha spicata/química , Monoterpenos/aislamiento & purificación , Monoterpenos/farmacología , Aceites Volátiles/síntesis química , Aceites Volátiles/aislamiento & purificación , Compuestos Epoxi/química , Humanos , Conformación Molecular , Monoterpenos/química , Fitoterapia , Estereoisomerismo , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Total syntheses of pyocyanin, lavanducyanin, and marinocyanins A and B have been accomplished. The N-substituted phenazin-1-one skeleton, a common framework of these natural products, was constructed through the oxidative condensation of pyrogallol with N-substituted benzene-1,2-diamine under an oxygen atmosphere in a single step. Regioselective bromination with N-bromosuccinimide at the C-2 position of N-alkylated phenazin-1-ones afforded brominated natural products.