RESUMO
Basidalin, isolated from the basidiomycete Leucoagaricus naucina, has previously demonstrated antibacterial and antitumor properties against murine cancer cells in vivo, but its effects on human cancer cells remain unknown. In this study, we found that basidalin possesses antiproliferative activity against human cancer cell lines. To elucidate the antiproliferative mechanism of basidalin, we focused on autophagy. Treatment with basidalin led to an increase in LC3-II expression level, and accelerated autophagic flux through an mTOR-independent pathway. Moreover, according to the structure-activity relationship analysis-including newly synthesized basidalin analogs-the formyl group, not the amino group, contributes to the antiproliferative activities of basidalin against human cancer cells. Additionally, the antiproliferative activity of basidalin analogs was strongly correlated with autophagy-inducing activity, indicating that basidalin exhibits antiproliferative activity through autophagy induction. These data suggest that basidalin, characterized by its ability to upregulate autophagic flux, emerges as a novel anticancer drug.
Assuntos
Antineoplásicos , Autofagia , Furanos , Animais , Humanos , Camundongos , Antineoplásicos/farmacologia , Apoptose , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Furanos/farmacologiaRESUMO
An effective method was developed for TfOH-catalyzed construction of spiroindanes and spirotetralines containing an all-carbon quaternary stereocenter. Intramolecular Friedel-Crafts-type 1,4-addition of the substrates which were di- or trimethoxybenzene and 2-cyclohexenone linked by an alkyl chain proceeded smoothly in the presence of 30â mol % of TfOH. A variety of spiroindanes and spirotetralines were obtained with moderate to excellent yield by this method. The reaction was successfully applied in the first total synthesis of the unusual proaporphine alkaloid (±)-misrametine, which included the gram-scale spirocyclization and selective O-demethylation used KCN in DMSO condition as key steps.
Assuntos
Alcaloides , Antineoplásicos , Estrutura Molecular , Catálise , Dimetil Sulfóxido , CarbonoRESUMO
A highly stereoselective (3 + 2) cycloaddition for the asymmetric synthesis of versatile cyclopentene compounds containing all-carbon quaternary stereocenters was developed. The phosphine-catalyzed reactions of alkynoates with α-alkylated electron-deficient alkenes bearing Oppolzer's camphorsultam showed high to excellent diastereoselectivities and perfect regioselectivities. The usefulness of this reaction was demonstrated in the concise formal synthesis of (R)-(-)-puraquinonic acid.
Assuntos
Carbono , Ciclopentanos , Reação de Cicloadição , Indenos , EstereoisomerismoRESUMO
Humulanolides are natural products isolated from Asteriscus, and the isolation and total synthesis of many types of humulanolides have been reported. In this study, we evaluated anti-proliferative activity of twelve humulanolides against various human cancer cell lines and found that humulanolide analog E, which was newly designed and synthesized, exhibited the highest anti-proliferative activity. Structure-activity relationship analysis revealed that α,ß-unsaturated carbonyl moieties in humulanolides play an important role for anti-proliferative activity. To identify molecular targets of humulanolide analog E, we investigated various cell-based and in vitro assays. Treatment with humulanolide analog E against human fibrosarcoma HT1080 cells increased the expression level of HSP70 protein and decreased the levels of AKT and CDK4, which are HSP90 client proteins. Moreover, humulanolide analog E inhibited refolding of denatured luciferase protein via suppression of HSP90 activity in vitro. These results suggest that humulanolide analog E possesses the anti-proliferative activity against human cancer cells by inhibiting HSP90 functions.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Asteraceae/química , Produtos Biológicos/farmacologia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
A diaryliodonium salt-based strategy enabled the first systematic synthesis of rarely accessible N-alkoxyindolines. Mechanistic analyses suggested that the reaction likely involves reductive elimination of iodobenzene from iodaoxazepine via a four-membered transition state, followed by Meisenheimer rearrangement. Substrates with N-carbamate protection afforded indole in a manner similar to that of the Ishikawa indole synthesis. Preinstallation of a stannyl group as an iodonium salt precursor greatly expanded the substrate scope, and further mechanistic insights are discussed.
Assuntos
Carbamatos , Resolução de Problemas , IndóisRESUMO
Highly enantioselective organocatalytic construction of spirochromans containing a tetrasubstituted stereocenter was developed. Intramolecular oxy-Michael addition was catalyzed with a bifunctional cinchona alkaloid thiourea catalyst. A variety of spirochroman compounds containing a tetrasubstituted stereocenter were obtained with excellent enantioselectivities of up to 99% enantiomeric excess. The reaction was applied to the asymmetric formal synthesis of (-)-(R)-cordiachromene.
RESUMO
Two stereocontrolled routes to the tricyclic core of (-)-callophycoic acid A are described. Our synthetic strategy relied on stereoselective allylboration using a new allylboronate reagent to construct the all-carbon quaternary stereocenter in the core, followed by efficient radical cyclization or palladium-catalyzed reductive cyclization to form its multisubstituted cyclohexane ring. The tetrahydrooxepin ring was constructed by intramolecular etheration. This study provides the first method for the stereoselective synthesis of the characteristic tricyclic skeleton of callophycoic acids.
RESUMO
Vibsanin A is the first natural product isolated from Viburnum awabuki and has several biological activities. We have reported that a vibsanin A analog, obtained from process of total synthesis of vibsanin A, has anti-proliferative activity against human cancer cell lines. In this study, we evaluated anti-proliferative effect of the vibsanin A analogs against various human cancer cell lines and examined molecular target of the analog in human cells. Among the vibsanin A analogs, vibsanin A analog C (VAC) showed anti-proliferative effect against various cancer cell lines, and the anti-proliferative activity was strongest among the vibsanin A analogs. Additionally, VAC fluctuated amounts of HSP90-related proteins in cells and inhibited HSP90-mediated protein refolding of luciferase in vitro. These results suggest that the anti-proliferative activity of VAC is due to HSP90 inhibition, and VAC has a potential as novel anti-cancer drug as HSP90 inhibitor.
Assuntos
Antineoplásicos/farmacologia , Diterpenos/farmacologia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Diterpenos/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Estrutura Molecular , Redobramento de Proteína/efeitos dos fármacos , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
Cytosporolide (Cytos) A-C, isolated from the fungus Cytospora sp., have anti-microbial activity, but their molecular targets in mammalian cells are unknown. We have previously reported the total synthesis of Cytos A by biomimetic hetero-Diels-Alder reaction. In this study, to examine the novel bioactivity of Cytos, we synthesized Cytos C and measured cell growth-inhibiting activities of 7 compounds, including Cytos A and C, in several human cancer cell lines. Among these compounds, Cytos C and tetradeoxycytosporolide A (TD-Cytos A), a model compound for the synthesis of Cytos A, had anti-proliferative effects on cancer cells, and TD-Cytos A exhibited stronger activity than Cytos C. In vitro topoisomerase-mediated DNA relaxing experiments showed that TD-Cytos A inhibited the activities of topoisomerase I and II, whereas Cytos C targeted only topoisomerase I. These data suggest that the anti-proliferative activities of Cytos correlate with the inhibition of topoisomerases and implicated TD-Cytos A as a novel anti-cancer drug that suppresses the activities of topoisomerase I and II.
Assuntos
Antineoplásicos/farmacologia , DNA Topoisomerases Tipo I/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/antagonistas & inibidores , Sesquiterpenos/farmacologia , Inibidores da Topoisomerase/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , DNA Topoisomerases Tipo II/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Sesquiterpenos/síntese química , Sesquiterpenos/química , Relação Estrutura-Atividade , Inibidores da Topoisomerase/síntese química , Inibidores da Topoisomerase/química , Células Tumorais CultivadasRESUMO
The short, efficient total synthesis of (+)-aquatolide was achieved by a biomimetic transannular [2+2] photocycloaddition, and provides the first example of constructing a 5/5/4/8-ring system from asteriscunolides. Furthermore, the reaction leading to a 5/4/4/7-ring system, the originally proposed structure of aquatolide, was also developed. This strategy achieved syntheses of five more humulanolides, (-)-asteriscunolidesâ A, C, D, and I, and (+)-tetradehydroasteriscanolide.
RESUMO
Clavilactones A, B, and D are epidermal growth factor receptor tyrosine kinase inhibitors that were isolated from cultures of the fungus Clitocybe clavipes. Here, we report full details of the total synthesis of these clavilactones. A key feature of our synthetic approach is a ring-opening/ring-closing metathesis strategy that allows the concise transformation of a cyclobutenecarboxylate into a γ-butenolide. Coupled with enantioselective Ti/BINOL-catalyzed alkynylation of a multisubstituted benzaldehyde and ring-closing metathesis of a diene-bearing silylene acetal to construct the 10-membered carbocycle, this strategy enabled the total synthesis of the natural enantiomers (+)-clavilactone A and (-)-clavilactone B. In addition, the correct structure of clavilactone D was determined by the synthesis of two newly proposed structures. This research resulted in the asymmetric synthesis of the revised (+)-clavilactone D.
RESUMO
A structural revision of clavilactoneâ D, a potent inhibitor of protein tyrosine kinases, was achieved by total syntheses of two newly proposed structures. The syntheses relied on ring-opening/ring-closing metathesis, which transformed a cyclobutenecarboxylate into a γ-butenolide. The syntheses confirmed that the correct structure of clavilactoneâ D has an amino group at C-3 instead of a hydroxy group at C-2 in the originally proposed structure.
Assuntos
Produtos Biológicos/síntese química , Lactonas/síntese química , Inibidores de Proteínas Quinases/síntese química , Proteínas Tirosina Quinases/antagonistas & inibidores , 4-Butirolactona/análogos & derivados , 4-Butirolactona/síntese química , 4-Butirolactona/química , Basidiomycota/química , Produtos Biológicos/química , Ciclobutanos/síntese química , Ciclobutanos/química , Lactonas/química , Inibidores de Proteínas Quinases/química , EstereoisomerismoRESUMO
Vibsanin A is an 11-membered vibsane diterpenoid and is reported to induce myeloid cell differentiation via activation of protein kinase C (PKC) without tumor-promoting activity. Therefore, vibsanin A is thought to be an attractive compound for acute myeloid leukemia (AML) therapy. In this study, we synthesized vibsanin A analogs and compared the activity of these compounds for PKC activation and myeloid cell differentiation. We found that the hydroxymethyl group in vibsanin A is an important substituent to induce differentiation of AML cells. Collectively, our results showed the biochemical features of vibsanin A and provided new insights into the development of new antileukemic drugs.
Assuntos
Diterpenos/farmacologia , Células Mieloides/efeitos dos fármacos , Proteína Quinase C/metabolismo , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Diterpenos/síntese química , Diterpenos/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Células Mieloides/patologia , Relação Estrutura-AtividadeRESUMO
The highly enantioselective organocatalytic construction of spiroindanes containing an all-carbon quaternary stereocenter by intramolecular Friedel-Crafts-type 1,4-addition is described. The reaction was catalyzed by a cinchonidine-based primary amine and accelerated by water and p-bromophenol. A variety of spiro compounds containing quaternary stereocenters were obtained with excellent enantioselectivity (up to 95 %â ee). The reaction was applied to the asymmetric formal synthesis of the spirocyclic natural products (-)-cannabispirenonesâ A and B.
RESUMO
The first total synthesis of (+)-cytosporolide A was achieved by a biomimetic hetero-Diels-Alder reaction of (-)-fuscoatrol A with o-quinone methide generated from (+)-CJ-12,373. The dienophile, highly oxygenated caryophyllene sesquiterpenoid (-)-fuscoatrol A, was synthesized from the synthetic intermediate in our previous total synthesis of (+)-pestalotiopsin A. The o-quinone methide precursor, isochroman carboxylic acid (+)-CJ-12,373, was synthesized through a Kolbe-Schmitt reaction and an oxa-Pictet-Spengler reaction. The hetero-Diels-Alder reaction of these two compounds proceeded with complete chemo-, regio-, and stereoselectivity to produce the complicated pentacyclic ring system of the cytosporolide skeleton. This total synthesis unambiguously demonstrates that natural cytosporolide A has the structure previously suggested.
Assuntos
Biomimética , Reação de Cicloadição , Sesquiterpenos/síntese químicaRESUMO
In organic chemistry, selecting mild conditions for transformations and saving energy are increasingly important for achieving sustainable development goals. Herein, we describe a red-light-mediated Barton decarboxylation using readily available red-light-emitting diodes as the energy source and zinc tetraphenylporphyrin as the catalyst, avoiding explosive or hazardous reagents or external heating. Mechanistic studies suggest that the reaction probably proceeds via Dexter energy transfer between the activated catalyst and the Barton ester. Furthermore, a one-pot wavelength-selective reaction within the visible light range is developed in combination with a blue-light-mediated photoredox reaction, demonstrating the compatibility of two photochemical transformations based on mechanistic differences. This one-pot process expands the limits of the decarboxylative Giese reaction beyond polarity matching.
RESUMO
We describe the total synthesis and structural determination of (+)-akaterpin (1), an inhibitor of phosphatidylinositol-specific phospholipase C (PI-PLC). The key features of the synthetic strategy include the resolution of ß,γ-unsaturated ketone (±)-2a with chiral sulfoximine 6. The absolute stereochemistry was determined by comparison of the specific optical rotation data of (+)-1 and (-)-1 with that of natural akaterpin.
Assuntos
Inibidores Enzimáticos/química , Triterpenos/química , Inibidores Enzimáticos/síntese química , Cetonas/química , Conformação Molecular , Fosfoinositídeo Fosfolipase C/antagonistas & inibidores , Fosfoinositídeo Fosfolipase C/metabolismo , Estereoisomerismo , Triterpenos/síntese químicaRESUMO
An asymmetric Claisen rearrangement using Oppolzer’s camphorsultam was developed. Under thermal conditions, a geraniol-derived substrate underwent the rearrangement with good stereoselectivity. The absolute configuration of the newly formed all-carbon quaternary stereocenter was confirmed by the total synthesis of (+)-bakuchiol from the rearrangement product.
Assuntos
Fenóis/síntese química , Acetatos/química , Hidrólise , Conformação Molecular , Oxirredução , Fenóis/química , Estereoisomerismo , Sulfonamidas/químicaRESUMO
Fluorescent carbon dots (CDs) represent a promising eco-friendly next-generation phosphor. However, most CDs exhibit broad photoluminescence (PL) spectra [full width at half-maximum (fwhm) over 60 nm]; few works on CDs with sharp PL spectra (fwhm less than 40 nm) have been reported. In addition, their syntheses and color tuning require harsh conditions of high temperatures, long reaction times, and high pressures with catalysts. Here, we successfully prepared narrow-bandwidth emissive CDs (fwhm of 27-40 nm) from phloroglucinol in a glycol solvent of 1,2-pentanediol at temperatures as low as 180 °C for a reaction duration of as short as 6 h under ambient conditions without any catalysts via an open reaction system in which dehydration and condensation reactions among phloroglucinol molecules were enhanced. We shifted the emission peak from 463 to 511 nm by selecting seven kinds of solvents with different polarities, that is, emission colors could be tuned from blue to green by taking advantage of fluorescence solvatochromism. The CD-dispersed polymer films showed a similar solvatochromic behavior and sharp PL spectra, verifying the feasibility of applying the CDs to displays with a wide color gamut.
RESUMO
An enantioselective total synthesis of both enantiomers of caryophyllene-type sesquiterpenoid pestalotiopsin A has been achieved, thereby establishing the absolute stereochemistry of natural (+)-pestalotiopsin A. Highlights of the synthesis include a [2 + 2] cycloaddition of N-propioloyl Oppolzer's camphorsultam and ketene dialkyl acetal and subsequent highly stereoselective 1,4-hydride addition/protonation, an aldol reaction of functionalized bicyclic lactone with aldehyde, an efficient intramolecular Nozaki-Hiyama-Kishi (NHK) reaction for the construction of the highly strained (E)-cyclononene ring, and a palladium-catalyzed reduction of allylic mesylate with retention of the E configuration.