RESUMO
Resveratrol oligomers, ranging from dimers to octamers, are formed through regioselective synthesis involving the phenoxy radical coupling of resveratrol building blocks, exhibiting remarkable therapeutic potential, including antidiabetic properties. In this study, we elucidate the mechanistic insights into the insulin secretion potential of a resveratrol dimer, (-)-Ampelopsin F (AmF), isolated from the acetone extract of Vatica chinensis L. stem bark in Pancreatic Beta-TC-6 cell lines. The AmF (50 µM) treated cells exhibited a 3.5-fold increase in insulin secretion potential as compared to unstimulated cells, which was achieved through the enhancement of mitochondrial membrane hyperpolarization, elevation of intracellular calcium concentration, and upregulation of GLUT2 and glucokinase expression in pancreatic Beta-TC-6 cell lines. Furthermore, AmF effectively inhibited the activity of DPP4, showcasing a 2.5-fold decrease compared to the control and a significant 6.5-fold reduction compared to the positive control. These findings emphasize AmF as a potential lead for the management of diabetes mellitus and point to its possible application in the next therapeutic initiatives.
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Flavonoides , Células Secretoras de Insulina , Secreção de Insulina , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Resveratrol , Glucoquinase/metabolismo , Glucose/metabolismoRESUMO
The carbonyl moiety is one of the indispensable sub-units in organic synthesis with significant applications in medicinal as well as materials chemistry. Hence the insertion of a carbonyl group via simple and highly efficient routes has been one of the most challenging tasks for organic chemists. Though the direct utilisation of CO gas in carbonylation is the fundamental procedure for the construction of carbonyl compounds, it has certain drawbacks due to its toxic and explosive nature. As a result, the need for cheap and efficient CO surrogates has gained much attention nowadays by which CO gas can be easily generated in situ or ex situ. In this review we discuss the advantages of chloroform as CO surrogate and have surveyed recent carbonylation reactions where chloroform has been used as CO source.
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Pentafulvenes are a unique class of compounds that originally attracted attention due to their propensity to display nonbenzenoid aromaticity. Subsequently, they were recognized as valuable synthons for the construction of a wide range of compounds by virtue of their ability to display multiple cycloaddition profiles. Naturally, this area of organic chemistry has experienced rapid growth over the last five decades, fueled by elegant work showcasing the unique reactivity of pentafulvenes in a plethora of cycloaddition reactions. In this Review, we have attempted to provide a systematic account of the methods for the generation of pentafulvenes, their rich and varied cycloaddition chemistry, organometallic reactions, and theoretical studies that support their versatility. Further, we have highlighted their applications in the synthesis of a variety of complex structural frameworks. It is our conviction that this Review will be useful to a wide range of chemists, and will spur further research in this promising area.
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A palladium-catalyzed aminocarbonylation strategy exploiting chloroform as a CO source has been developed for the synthesis of biologically potent 2-amidoimidazopyridine scaffolds. The aminocarbonylation reaction was found to be general with a range of amines and substituted imidazopyridines. Preliminary biological evaluation of cytotoxicity on selected examples provides scope for future investigations.
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Phytochemical investigation of the stem bark of Myristica fatua Houtt. led to the isolation of a new compound 1 (3-tridecanoylbenzoic acid), along with six known acylphenols (2-7). All the compounds displayed moderate inhibitory activity on α-amylase and significant activity on α-glucosidase; however malabaricone B (6) and C (7) were identified as potent α-glucosidase inhibitors with IC50 values of 63.70⯱â¯0.546, and 43.61⯱â¯0.620⯵M respectively. Acylphenols (compounds 3-7) also showed significant antiglycation property. The molecular docking and dynamics simulation studies confirmed the efficient binding of malabaricone C with C-terminus of human maltase-glucoamylase (2QMJ). Malabaricone B also enhanced the 2-NBDG [2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxy glucose] uptake in L6 myotubes. These findings demonstrate that acylphenols isolated from Myristica fatua Houtt. can be considered as a lead scaffold for the treatment of type II diabetes mellitus.
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Inibidores de Glicosídeo Hidrolases/química , Hipoglicemiantes/química , Myristicaceae/química , Compostos Fitoquímicos/química , Sítios de Ligação , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/patologia , Inibidores de Glicosídeo Hidrolases/metabolismo , Inibidores de Glicosídeo Hidrolases/farmacologia , Humanos , Hipoglicemiantes/metabolismo , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Simulação de Dinâmica Molecular , Células Musculares/citologia , Células Musculares/efeitos dos fármacos , Células Musculares/metabolismo , Myristicaceae/metabolismo , Compostos Fitoquímicos/metabolismo , Compostos Fitoquímicos/farmacologia , Casca de Planta/química , Casca de Planta/metabolismo , Extratos Vegetais/química , Caules de Planta/química , Caules de Planta/metabolismo , Estrutura Terciária de Proteína , Resorcinóis/química , Resorcinóis/metabolismo , Resorcinóis/farmacologia , alfa-Glucosidases/química , alfa-Glucosidases/metabolismoRESUMO
The described titanium-catalyzed hydroalumination of conjugated dienes opens up a new way to allylaluminium reagents. The reaction is carried out by using diisobutylaluminium hydride (DIBAL-H) and a catalytic amount of [Cp2TiCl2] (Cp = cyclopentadienyl). When applied to mono- and disubstitued pentafulvenes, this reaction proceeds in a highly endocyclic manner. The formed allylaluminium compounds react regio- and stereoselectively with both aldehydes and ketones to afford homoallylic alcohols that are suitable synthons for functionalized cyclopentanones. An extension of this methodology to simple dienes was also investigated. In the proposed mechanism, the initially formed bimetallic species (Ti/Al) are involved in the two possible catalytic cycles with a direct hydroalumination or/and a hydrotitanation followed by a titanium to aluminium transmetallation.
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Herein we describe our efforts on the Lewis acid catalyzed stereoselective ring-opening of pentafulvene derived diazabicyclic olefins using various ortho-functionalized aryl iodides such as 2-iodoanilines, 2-iodophenols and 2-iodobenzene thiols to access trans-1,2 disubstituted alkylidenecyclopentenes. The scope of the reaction was also explored with a range of easily available aromatic and aliphatic alcohols. Furthermore, the palladium catalyzed intramolecular Heck cyclization of trans-1,2 disubstituted alkylidenecyclopentenes would provide an easy approach for the synthesis of highly functionalized spiropentacyclic frameworks consisting of a cyclopentene fused to an indoline/benzothiophene and pyrazolidine.
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Osteoporosis is a common metabolic old age disorder characterised by low bone mass content (BMC) and mineral density (BMD) with micro-architectural deterioration of the extracellular matrix, further increasing bone fragility risk. Several traditional remedies, including plant extracts and herbal formulations, are used worldwide by local healers to improve the overall bone health and metabolism as an excellent osteoregenerative agent. Pteropsermum rubiginosum is an underexplored medicinal plant used by tribal peoples of Western Ghats, India, to treat bone fractures and associated inflammation. The proposed study evaluates the elemental profiling and phytochemical characterisation of P. rubiginosum methanolic bark extract (PRME), along with detailed In vitro and In vivo biological investigation in MG-63 cells and Sprague-Dawley (SD) rats. AAS and ICP-MS analysis showed the presence of calcium, phosphorus, and magnesium and exceptional levels of strontium, chromium, and zinc in PRME. The NMR characterisation revealed the presence of vanillic acid, Ergost-4-ene-3-one and catechin. The molecular docking studies revealed the target pockets of isolated compounds and various marker proteins in the bone remodelling cycle. In vitro studies showed a significant hike in ALP and calcium content, along with upregulated mRNA expression of the ALP and COL1, which confirmed the osteoinductive activity of PRME in human osteoblast-like MG-63 cells. The in vivo evaluation in ovariectomised (OVX) rats showed remarkable recovery in ALP, collagen and osteocalcin protein after 3 months of PRME treatment. DEXA scanning reports in OVX rats supported the above in vitro and in vivo results, significantly enhancing the BMD and BMC. The results suggest that PRME can induce osteogenic activity and enhance bone formation with an excellent osteoprotective effect against bone loss in OVX animals due to estrogen deficiency. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-024-03942-7.
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ETHNOPHARMACOLOGICAL RELEVANCE OF STUDY: Pterospermum rubiginosum is an evergreen plant in Western Ghats, India, used by traditional tribal healers due to its excellent biological potential for treating inflammation and pain relief procedures. The bark extract is also consumed to relieve the inflammatory changes at the bone fractured site. The traditional medicinal plant in India have to be characterized for its diverse phytochemical moieties, its interactive multiple target sites, and to reveal the hidden molecular mechanism behind the biological potency. AIM OF THE STUDY: The study focussed on plant material characterization, computational analysis (prediction study), toxicological screening (In vivo), and anti-inflammatory evaluation of P. rubiginosum methanolic bark extracts (PRME) in LPS-induced RAW 264.7 cells. MATERIALS AND METHODS: The pure compound isolation of PRME and their biological interactions were used to predict the bioactive components, molecular targets, and molecular pathways of PRME in inhibiting inflammatory mediators. The anti-inflammatory effects of PRME extract were evaluated in the lipopolysaccharide (LPS)-induced RAW264.7 macrophage cell model. The toxicity evaluation of PRME was performed in healthy 30 Sprague-Dawley experimental rats, were randomly divided into five groups for toxicological evaluation for 90 days. The tissue levels of oxidative stress and organ toxicity markers were measured using the ELISA method. Nuclear magnetic resonance spectroscopy (NMR) was performed to characterize the bioactive molecules. RESULTS: Structural characterization revealed the presence of vanillic acid, 4-O-methyl gallic acid, E-resveratrol, gallocatechin, 4'-O-methyl gallocatechin, and catechin. Molecular docking of NF-kB exhibited significant interactions with vanillic acid and 4-O-methyl gallic acid with binding energy -351.159 Kcal/Mol and -326.5505 Kcal/Mol, respectively. The PRME-treated animals showed an increase in total GPx and antioxidant levels (SOD and catalase). Histopathological examination revealed no variation in the liver, renal and splenic tissue's cellular pattern. PRME inhibited the pro-inflammatory parameters (IL-1ß, IL-6, and TNF-α) in LPS-induced RAW 264.7 cells. The protein level of TNF-α and NF-kB protein expression study brought out a notable reduction and exhibited a good correlation with the gene expression study. CONCLUSION: The current study establishes the therapeutic potential of PRME as an effective inhibitory agent against LPS-activated RAW 264.7 cells induced inflammatory mediators. Long-term toxicity evaluation on SD rats confirmed the non-toxic nature of PRME up to 250mg/body weight for 3 months.
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NF-kappa B , Extratos Vegetais , Ratos , Animais , NF-kappa B/metabolismo , Extratos Vegetais/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Lipopolissacarídeos/farmacologia , Casca de Planta/química , Simulação de Acoplamento Molecular , Ácido Vanílico/análise , Ácido Vanílico/uso terapêutico , Ratos Sprague-Dawley , Anti-Inflamatórios/farmacologia , Inflamação/tratamento farmacológico , Mediadores da Inflamação/metabolismo , Ácido Gálico/análiseRESUMO
BACKGROUND: Nayopayam kwatha (NK) is a well-known polyherbal formulation widely used to cure respiratory ailments, heart problems, and postnatal difficulties. Literature suggests that so far no standardization protocol was developed for NK to validate its quality and purity. OBJECTIVE(S): To develop a standardization protocol for NK based on the marker phytoconstituents present in the individual herbs of the formulation. MATERIALS AND METHODS: The roots of bala [Sida cordifolia (B1) and Sida retusa (B2)], seeds of jeeraka (Cuminum cyminum), and rhizomes of nagara (Zingiber officinale) were the ingredients of NK. Since there were two source plants for bala, two sets of NK (NKB1 and NKB2) were prepared in the ratio 3:2:1 as per Vaidya Manorama and 10:1:1 as per Arogyaraksha Kalpadruma along with 1:1:1 as per the general way of Ayurvedic polyherbal decoctions. Both the individual herbs and the kwatha (decoction) prepared were analyzed in terms of pharmacognostical, organoleptic, and physcicochemical parameters as per the standard methods. Phytochemical analysis of the individual herbs resulted in the isolation of major phytoconstituents and the kwatha was quantified in terms of marker compounds with the aid of HPLC. RESULTS: HPLC quantification suggests that appreciable amount of marker phytoconstituents of individual herbs are present in the kwatha. Thus, the isolated compounds luteolin (C. cyminum), 6-gingerol (Z. officinale), ß-sitosterol (S. retusa), and ecdysterone (S.cordifolia) can be used as markers to standardize NK. CONCLUSION: Characteristics of NK, as well as its individual drugs, were well-established. The present study of NK with respect to its phytochemistry revealed that the classical drug ratios of the polyherbal formulation are of utmost importance rather than the ingredients in equal proportion. The characterization parameters of individual herbs and kwatha described in this study may serve as a standard reference for quality control analysis of NK and the method developed in this study can be used as a reliable technique for standardization of NK to ensure the purity and quality of raw drugs used.
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The complete mitochondrial genome of the near threatened mahseer fish, Neolissochilus hexastichus, was characterized for the first-time using Ion Torrent NGS platform. The total length of the mitogenome was 16,538 bp including a standard set of 22 transfer RNAs (tRNAs), 2 ribosomal RNAs (rRNAs), 13 protein-coding genes and a non-coding control region. Twenty-eight of the 37 genes are located on the light strand and, the remaining nine genes are situated on the heavy strand. Phylogenetic analysis showed the sister relationship between N. hexastichus and N. hexagonolepis. The mitogenome could be useful for phylogenetics, population genetics, and conservation of the mahseers.
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Promalabaricone B (PMB), an acylphenol was isolated from dichloromethane-soluble extract of the seeds of Myrisitica fatua Houtt. PMB exhibited significant inhibitory activity on α-glucosidase enzyme. The molecular docking and dynamics studies of PMB with human maltase-glucoamylase were performed. PMB exhibited an enhanced glucose uptake in L6 myotubes with 46.3% in 2.5 µM. Encouraged with these results; we investigated the molecular mechanism of PMB through the upregulation of AMPK. The results revealed that PMB promoted the glucose uptake in myocytes by stimulating the translocation and expression of GLUT4. From this, it is clear that PMB can acts as a potential therapeutic option for diabetes treatment, and its hypoglycaemic effect may be mediated by AMPK upregulation and induction of GLUT4 translocation.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Glucose/metabolismo , Hipoglicemiantes/farmacologia , Fibras Musculares Esqueléticas/metabolismo , Myristica/química , Fenóis/farmacologia , Sementes/química , Regulação para Cima/efeitos dos fármacos , Animais , Transporte Biológico/efeitos dos fármacos , Transportador de Glucose Tipo 4/metabolismo , Glicosilação/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fenóis/química , Fenóis/isolamento & purificação , Saccharomyces cerevisiae/enzimologia , Transdução de Sinais/efeitos dos fármacos , Suínos , alfa-Amilases/metabolismo , alfa-Glucosidases/metabolismoRESUMO
Phytochemical investigation of the stem bark of Hopea parviflora resulted in the isolation of 9 compounds; which includes friedelin (1), friedelin-3ß-ol (2), (-)-ampelopsin A (3), (-)-É-viniferin (4), (-)-hopeaphenol (5), vaticaphenol A (6), 2,4,8-trihydroxyphenanthrene-2-O-glucoside (7), ellagic acid-3,3',4-trimethoxy-4'-O-α-L-rhamnopyranoside (8) and ß-sitosterol-ß-D-glucoside (9). Among them, compounds 1, 2, 6, 7, 8 and 9 are isolated for the first time from this species. Further, we evaluated the anti-inflammatory activity of compounds 4, 5, 6, 7 and 8. In this study, compound 8 inhibited the activity of proinflammatory mediators like NO, TNF-α, IL-6, 5-LOX and COX-2, also promoted the action of anti-inflammatory mediator like IL-10 via inhibition of the NF-κB pathway in LPS-stimulated RAW 264.7 macrophages.
Assuntos
Anti-Inflamatórios/farmacologia , Dipterocarpaceae , Ácido Elágico/farmacologia , Animais , Anti-Inflamatórios/isolamento & purificação , Dipterocarpaceae/química , Ácido Elágico/isolamento & purificação , Lipopolissacarídeos , Macrófagos/efeitos dos fármacos , Camundongos , NF-kappa B , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Casca de Planta/química , Células RAW 264.7RESUMO
A novel palladium catalyzed protocol for the synthesis of cyclopentene fused heterocycles from diazabicyclic alkenes and ortho-functionalized aryliodides has been elaborated. The reaction can be tuned toward the formation of either 3,4-disubstituted cyclopentenes or cyclopentene fused heterocycles by careful manipulation of the reaction parameters. A number of cyclopentene fused benzofurans and indole derivatives were prepared in excellent yield by utilizing the developed methodology.
RESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Hopea ponga (Dennst.) Mabb. Is used in traditional herbal formulations for diabetes complications. The aim of this study is to evaluate the antidiabetic effect of extracts and compounds from H. ponga. MATERIALS AND METHODS: Silica gel column chromatography was performed to identify various chemical components of the plant extract. Different extracts of H. ponga and isolated compounds were screened for their antidiabetic effect by modulation of digestive enzymes and protein glycation. The effect of glucose uptake by the compounds and the pathways through which the compounds mediate the glucose uptake potential were confirmed by fluorescent microscopy, flow cytometry and western blot analysis. RESULTS: Acetone and ethanol extracts of the stem bark of Hopea ponga (Dennst.) Mabb. Afforded six resveratrol oligomers namely, E-resveratrol (1), (-)-ε-viniferin (2), (-)-α-viniferin (3), trihydroxyphenanthrene glucoside (THPG) (4), vaticaphenol A (5), (-)-hopeaphenol (6), along with four phytosterols. The structures were determined on the basis of spectroscopic analyses including nuclear magnetic resonance (NMR) spectroscopy and high resolution mass spectrometry (HRMS) data. Compounds 1-5 and 7-10 were tested for their α-glucosidase, α-amylase and glycation inhibitiory activities. All the resveratrol oligomers (1-5) showed prominent α-glucosidase inhibition with IC50 values, 12.56⯱â¯1.00, 23.98⯱â¯1.11, 7.17⯱â¯1.10, 31.74⯱â¯0.42 and 16.95⯱â¯0.39⯵M, respectively. Molecular docking studies also supported the observed α-glucosidase inhibition. Compound 3 displayed IC50 values of 4.85⯱â¯0.06 and 27.10⯱â¯0.04⯵M in α-amylase and glycation inhibitory assays activity. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay revealed that the compounds 3 and 4 were found to be less toxic at a concentration of 100⯵M (<10%) and 25⯵M (<20%), respectively. The effect of glucose uptake performed by 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose (2-NBDG) in L6 myoblast were measured by fluorescent microscopy and flow cytometry. The compounds 3 and 4 showed 2-NBDG uptake of 49.6% and 38.8% respectively. By examining the molecular pathway through which the compounds elicit their glucose uptake potential, it was observed that both the compounds mainly act via AMPK pathway. CONCLUSION: This is the first report on the isolation of compounds from H. ponga. Altogether, the results of this study reveal the antidiabetic effects of H. ponga extracts and isolated compounds promoting traditional use of this plant in the treatment of diabetes.
Assuntos
Dipterocarpaceae/química , Hipoglicemiantes/farmacologia , Extratos Vegetais/farmacologia , Resveratrol/farmacologia , Acetona/química , Animais , Linhagem Celular , Diabetes Mellitus/tratamento farmacológico , Ensaios Enzimáticos , Etanol/química , Glicosilação/efeitos dos fármacos , Hipoglicemiantes/química , Hipoglicemiantes/isolamento & purificação , Concentração Inibidora 50 , Medicina Tradicional/métodos , Simulação de Acoplamento Molecular , Estrutura Molecular , Mioblastos , Casca de Planta/química , Extratos Vegetais/química , Caules de Planta/química , Ratos , Resveratrol/química , Resveratrol/isolamento & purificação , Testes de Toxicidade , alfa-Amilases/antagonistas & inibidores , alfa-Amilases/química , alfa-Amilases/metabolismo , alfa-Glucosidases/química , alfa-Glucosidases/metabolismoRESUMO
A Pd-catalyzed synthesis of 3,4,5-trisubstituted cyclopentenes from diazabicyclic olefins and o-iodobenzoates has been developed. The hitherto unknown cascade process involves three stages: carbopalladation, oxypalladation and a Tsuji-Trost reaction. We have also developed a facile route involving a novel benzylic C-H activation towards cyclopentenoindane moieties.
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A newly synthesised zerumbone pendant derivative (ZPD) was studied in human cervical cancer cells (HeLa) for its anticancer properties. ZPD significantly inhibited the growth of human cervical cancer cells with a GI50 value of 6.35 ± 1.30 µM, which also induced morphological changes and apoptosis in a dose-dependent manner. Our data indicated that ZPD actively encouraged programmed cell death in HeLa cells which were confirmed by DNA fragmentation, phosphatidylserine translocation, increased activity of caspase 3, upregulation of the expression of the pro-apoptotic protein Bax, cleaved PARP, cleaved caspase 3 and downregulation of anti-apoptotic protein Bcl-2. ZPD also inhibited cell migration of HeLa cells, decreasing the production of MMP-2,-9 and downregulation of expression of MMPs and pro-angiogenic factor VEGF. Also it is nontoxic to normal rat cardiac myoblasts. Overall, ZPD is a promising candidate for inducing cytotoxicity, apoptosis and anti-migratory effects in cervical cancer cells.
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Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Sesquiterpenos/farmacologia , Antineoplásicos/química , Caspase 3/metabolismo , Movimento Celular/efeitos dos fármacos , Fragmentação do DNA/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Feminino , Células HeLa , Humanos , Microscopia de Fluorescência , Paclitaxel/toxicidade , Fosfatidilserinas/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Sesquiterpenos/química , Regulação para Cima/efeitos dos fármacos , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia , Proteína X Associada a bcl-2/metabolismoRESUMO
An efficient stereoselective route for the synthesis of cyclopentene fused 2-pyrrolines has been established via a Pd-catalyzed C-H activation/oxidative coupling of aryl enamides with diazabicyclic olefins. The proposed two-stage mechanism was successfully proven by isolating the intermediate trans-disubstituted cyclopentene.
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Novel glycoconjugated squaraine dyes were synthesized, which exhibited excellent internalization in tumor cells and are potent fluorogenic imaging probes for tumor selective optical imaging.
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Corantes/síntese química , Ciclobutanos/química , Neoplasias/diagnóstico por imagem , Imagem Óptica/métodos , Fenóis/química , Linhagem Celular , Corantes/química , Humanos , Estrutura Molecular , Análise Espectral , Coloração e RotulagemRESUMO
Bicyclic hydrazines undergo a facile palladium/iodine mediated stereoselective ring opening on reaction with organoboronic acids affording trans-3,4-disubstituted hydrazino cyclopentenes in good to excellent yield.