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This contribution describes the development of chemoenzymatic one-pot processes, which combine an oxidative rearrangement and a biotransformation catalyzed by an imine reductase (IRED), for the synthesis of highly enantiomerically enriched secondary amines, such as an aryl-substituted pyrrolidine and a benzazepine. The benefits of this chemoenzymatic one-pot approach include high overall conversions (up to >99%), high enantiomeric excesses (up to >99% ee), and a straightforward synthetic approach toward secondary amines without the need to isolate the formed intermediate. For the initial chemical reaction, namely, the oxidative rearrangement, PhI(OAc)2 in methanol is used as a non-natural reagent, whereas the enzymatic step requires only stoichiometric amounts of d-glucose along with catalytic amounts of IRED, glucose dehydrogenase (GDH), and the cofactor NADPH. This methodology, demonstrating the compatibility of a "classic" organic synthesis using a non-natural, highly reactive reagent and a subsequent biocatalytic step, can be applied for different amines as substrates, thus making this concept a versatile tool in synthetic organic chemistry in general and for enantioselective synthesis of heterocyclic secondary amines in particular.
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Bis-indole alkaloids from marine sponges are an intriguing class of natural products with a variety of activities. However, only a preliminary biological study of tulongicin A (5), a related previously isolated marine tris-indole alkaloid, has been conducted. In this study, we accomplished the first asymmetric total synthesis of 5 via the construction of an imidazoline-linked bis-indolylmethane skeleton using a Friedel-Crafts-type reaction. Our synthesis enabled a detailed study of the antibacterial profile of 5. Compound 5 displayed bactericidal activity against Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA) strains.
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Antibacterianos , Alcaloides Indólicos , Staphylococcus aureus Resistente a Meticilina , Pruebas de Sensibilidad Microbiana , Staphylococcus aureus , Antibacterianos/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Estructura Molecular , Alcaloides Indólicos/farmacología , Alcaloides Indólicos/síntesis química , Alcaloides Indólicos/química , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Animales , Staphylococcus aureus/efectos de los fármacos , Poríferos/química , Biología MarinaRESUMEN
We report a perchloric acid-catalyzed heteroannulation for the synthesis of spirocyclobutanes using vinyloxyphenylbicyclobutanes with water. This metal-free reaction yields high product outputs and is consistent with the formation of a cyclobutene intermediate originating from an isomerization of a bicyclobutane.
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The adjustment of the main helical scaffold in helicenes is a fundamental strategy for modulating their optical features, thereby enhancing their potential for diverse applications. This work explores the influence of helical elongation (n = 5-9) on the structural, photophysical, and chiroptical features of symmetric oxa[n]helicenes. Crystal structure analyses revealed structural variations with helical extension, impacting torsion angles, helical pitch, and packing arrangements. Through theoretical investigations using density functional theory (DFT) calculations, the impact of helical extension on aromaticity, planarity distortion, and heightened chiral stability were discussed. Photophysical features were studied through spectrophotometric analysis, with insights gained through time-dependent DFT (TD-DFT) calculations. Following optical resolution via chiral high-performance liquid chromatography (HPLC), the chiroptical properties of both enantiomers of oxa[7]helicene and oxa[9]helicene were investigated. A slight variation in the main helical scaffold of oxa[n]helicenes from [7] to [9] induced an approximately three-fold increase in dissymmetry factors with the biggest values of|glum| of oxa[9]helicene (2.2 × 10-3) compared to|glum|of oxa[7]helicene (0.8 × 10-3), findings discussed and supported by TD-DFT calculations.
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The fungal genus Trichoderma is a rich source of structurally diverse secondary metabolites with remarkable pharmaceutical properties. The chemical constituents and anticancer activities of the marine-derived fungus Trichoderma lixii have never been investigated. In this study, a bioactivity-guided investigation led to the isolation of eleven compounds, including trichodermamide A (1), trichodermamide B (2), aspergillazine A (3), DC1149B (4), ergosterol peroxide (5), cerebrosides D/C (6/7), 5-hydroxy-2,3-dimethyl-7-methoxychromone (8), nafuredin A (9), and harzianumols E/F (10/11). Their structures were identified by using various spectroscopic techniques and compared to those in the literature. Notably, compounds 2 and 5-11 were reported for the first time from this species. Evaluation of the anticancer activities of all isolated compounds was carried out. Compounds 2, 4, and 9 were the most active antiproliferative compounds against three cancer cell lines (human myeloma KMS-11, colorectal HT-29, and pancreas PANC-1). Intriguingly, compound 4 exhibited anti-austerity activity with an IC50 of 22.43 µM against PANC-1 cancer cells under glucose starvation conditions, while compound 2 did not.
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Antineoplásicos , Trichoderma , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Humanos , Trichoderma/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Estructura Molecular , Organismos Acuáticos/química , Ensayos de Selección de Medicamentos AntitumoralesRESUMEN
A novel chiral borinic acid (CBA), an organocatalyst possessing a binaphthyl skeleton, was designed and synthesized. The synthesis of CBA was achieved with a 72% yield in four steps starting with optically pure 1,1'-bi-2-naphthol. The asymmetric catalytic activity was investigated in the desymmetrization of meso-1,2-diol.
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Transgenic luciferase-expressing Plasmodium falciparum parasites have been widely used for the evaluation of anti-malarial compounds. Here, to screen for anti-malarial drugs effective against multiple stages of the parasite, we generate a P. falciparum reporter parasite that constitutively expresses NanoLuciferase (NanoLuc) throughout its whole life cycle. The NanoLuc-expressing P. falciparum reporter parasite shows a quantitative NanoLuc signal in the asexual blood, gametocyte, mosquito, and liver stages. We also establish assay systems to evaluate the anti-malarial activity of compounds at the asexual blood, gametocyte, and liver stages, and then determine the 50% inhibitory concentration (IC50) value of several anti-malarial compounds. Through the development of this robust high-throughput screening system, we identify an anti-malarial compound that kills the asexual blood stage parasites. Our study highlights the utility of the NanoLuc reporter line, which may advance anti-malarial drug development through the improved screening of compounds targeting the human malarial parasite at multiple stages.
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Antimaláricos , Humanos , Animales , Antimaláricos/farmacología , Plasmodium falciparum/genética , Animales Modificados Genéticamente , BioensayoRESUMEN
Sulfonyl indoles were synthesized by migratory cycloisomerization from the allene N-tosyl-o-allenylaniline. 3-Tosyl indoles or 4-tosyl indoles were selectively produced using a Pd catalyst or a Au catalyst, respectively.
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We designed and synthesized novel 4-acetoxypentanamide derivatives of spliceostatin A, whose 4-acetoxypentenamide moiety is reduced (7), isomerized (8), or substituted with methyl at the α-position (9). The results of biological evaluation against AR-V7 and the docking analysis of each derivative suggest that the geometry of the 4-acetoxypentenamide moiety of spliceostatin A is important for its biological activity.
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Neoplasias de la Próstata , Compuestos de Espiro , Masculino , Humanos , Neoplasias de la Próstata/tratamiento farmacológico , Piranos , Receptores Androgénicos , Isoformas de ProteínasRESUMEN
Structurally simplified analogues of ansellone A, in which the decalin skeleton is replaced with a lipophilic chain, were prepared and their HIV latency-reversing activities biologically evaluated. In particular, two analogues bearing ether and alkenyl side chains, respectively, showed comparable activities to that of ansellone A. Each of the simplified compounds was easily synthesized using Prins cyclisation chemistry.
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Infecciones por VIH , Humanos , Relación Estructura-ActividadRESUMEN
We report the heteroannulations of bicyclobutane derivatives bearing enol ether groups in the presence of H2O under mild conditions. The reaction affords spirocyclobutanes with cyclic acetal groups via the Au-catalyzed hydration of the enol ether group and subsequent intramolecular cyclization.
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Migratory cycloisomerization using transition metal catalyst is useful for synthesizing substituted heterocyclic compounds. We achieved palladium-catalyzed migratory cycloisomerization of 3-o-alkynylphenoxy acrylic acid ester derivatives to give 2,3-disubstituted benzofurans. Although there are several reports of benzofuran synthesis with palladium-catalyzed migratory cycloisomerization, migratory groups are limited to allyl and propargyl groups. This report is the first example of benzofuran synthesis with palladium-catalyzed cycloisomerization of C(sp2)-O bond cleavage.
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Benzofuranos , Compuestos Heterocíclicos , Paladio/química , Benzofuranos/química , CatálisisRESUMEN
This paper provides the first report of the intramolecular [2+2] cycloaddition of vinylsilane. The [2+2] cycloaddition of allenes is a useful reaction that can synthesize cyclobutanes. However, no previous works have attempted to control the regioselectivity between the two double bonds of allenes only by changing the reaction conditions, although there have been some reports of the regioselective [2+2] cycloaddition of allenes by changing the substrate. In this study, we have succeeded in controlling intramolecular [2+2] cycloaddition reactions at the proximal and distal positions of allenes simply by changing the reaction conditions. We found that the atomic radius of silicon is very important for perfect control of the reaction's sites. The structures of all key compounds were determined by the crystal sponge method which could identify the structures of liquid compounds.
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A double ring expansion strategy for constructing fused 3-benzazepines is described. The oxidative ring expansion of spiroamine compounds with N-chlorosuccinimide and subsequent ring expansion of the resulting ketiminium ion intermediates with trimethylsilyldiazomethane afforded fused 3-benzazepines in a one-pot operation. Importantly, the Dolby-Weinreb enamine, which is a key synthetic intermediate for harringtonine alkaloids, cephalotaxines, can be accessed from commercial materials in only two steps using our developed method.
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Alcaloides , Benzazepinas , Estructura MolecularRESUMEN
The first total synthesis of marine sesterterpenoid ansellone G (2) was accomplished. This strategy utilizes the Prins cyclization reaction of a chloro-substituted homoallyl alcohol to synthesize the hydrobenzopyran skeleton. The preintroduction of the chloro groups facilitated the functional group transformation for 2 after constructing the carbon framework. Furthermore, we also successfully synthesized phorbadione (3) by dehydrating the tertiary alcohol. The HIV latency-reversing activity of the synthesized 2, 3, and deacetylated 2 was also evaluated.
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Alcoholes , CiclizaciónRESUMEN
Monoamine oxidase B (MAO-B) metabolizes monoamines such as dopamine regarding neural transmission and controls its level in the mammalian's brain. When MAO-B metabolizes dopamine abnormally, normal neurotransmission does not occur, and central nervous system disorders such as Parkinson's disease may develop. Although several MAO inhibitors have been developed, most of them have no selectivity between monoamine oxidase A (MAO-A) and MAO-B, or they work irreversibly against the enzyme. This report describes the first case of screening of N-arylated heliamine derivatives to develop novel MAO-B selective inhibitors that can be synthesized concisely by microwave-assisted Pd nanoparticle-catalyzed Buchwald-Hartwig amination. We discovered that the derivatives 4h, 4i, and 4j display inhibitory activity against MAO-B with IC50 values of 1.55, 13.5, and 5.08 µM, respectively.
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Multitasking single-catalyst systems that allow multiple chemical transformations within a single reaction vessel are important for the development of eco-compatible chemistry. Here, we have developed a rhodium-catalyzed system that transforms 1-(allyloxy)-2-(cyclopropylmethyl)benzene derivatives to 2-ethyl-3-isopropylbenzofurans via double isomerization/cycloisomerization/aromatization.
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Chemical diversification of substances present in natural product extracts can lead to a number of natural product-like compounds with a better chance of desirable bioactivities. The aim of this work was to discover unprecedented chemical conversion and produce new compounds through a one-step reaction of substances present in the extracts of marine sponges. In this report, a new unnatural tetracyclic bromopyrrole-imidazole derivative, rac-6-OEt-cylindradine A (1), was created from a chemically diversified extract of the sponge Petrosia (Strongylophora) sp. We also confirmed that 1 originated from naturally occurring (-)-cylindradine A (2) via a new reaction pattern. Moreover, (-)-dibromophakellin (3) and 4,5-dibromopyrrole-2-carboxylic acid (4), as well as 2, were reported herein for the first time in this genus. Studies on the possible reaction mechanism and bioactivities were also conducted. The results indicate that the direct chemical diversification of substances present in natural product extracts can be a speedy and useful strategy for the discovery of new compounds.
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Petrosia , Poríferos , Animales , Petrosia/química , Poríferos/química , ImidazolesRESUMEN
The absolute structure of an indole alkaloid (+)-cinchonaminone by total synthesis of both (+)-cinchonaminone and its enantiomer was determined. The main focus of the study was the enantioselective synthesis of both enantiomers of a chiral cis-3,4-disubstituted piperidine. We also evaluated monoamine oxidase (MAO) inhibitory activities of these enantiomers. Furthermore, its structurally simplified derivatives were synthesized that did not have any chiral center. Two of these derivatives showed stronger MAO inhibitory activities than that of (+)-cinchonaminone.
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The aim of this study was to evaluate bitterness by using "CCDP; Change in concentration-dependent potential" considering dose-dependency of active pharmaceutical ingredients (APIs) as new and useful bitterness evaluation index compared with bitter sensor output value which is conventional bitterness evaluation index for 48 pediatric medicines from the recent edition of the WHO model list of essential medicines for children (7th edn, 2019). Solutions (0.01, 0.03, 0.1 mM) of the compounds were evaluated by an artificial taste sensor using membranes sensitive to bitterness. The dose-response slope of the sensor outputs was defined as CCDP. On the basis of principal component analysis of CCDPs, chlorpromazine hydrochloride, amitriptyline hydrochloride, propranolol hydrochloride, primaquine phosphate and haloperidol were predicted to express the strongest levels of basic bitterness, surpassing that of quinine hydrochloride. Correlation analysis (Fisher's exact tests and multiple regression analysis) was performed to determine the relation between CCDPs and various physicochemical properties participated in hydrophilicity and hydrophobicity. It is revealed that contribution physicochemical factors are different by individual basic bitterness sensor (AC0, AN0 or BT0), and this result becomes the criterion of the sensor choice to evaluate basic bitterness intensity using basic bitterness sensors. Hydrophobic and hydrophilic interactions could be simulated by ligand docking modeling for haloperidol, miconazole and quinine hydrochloride. The pharmaceutical products need a bitterness evaluation in consideration of concentration-dependency to vary in a dose depending on a patient individual. Thus, it was concluded that CCDP correlated to hydrophilicity and hydrophobicity is useful as a bitterness evaluation index of APIs in pediatric medicines.