Molecules : A Journal of Synthetic Chemistry and Natural Product Chemistry最新文献

{"title":"A Novel Convergent Synthesis of the Potent Antiglaucoma Agent Tafluprost","authors":"M. Krupa, M. Chodyński, A. Ostaszewska, P. Cmoch, I. Dams","doi":"10.3390/molecules22020217","DOIUrl":"https://doi.org/10.3390/molecules22020217","url":null,"abstract":"Tafluprost (AFP-168, 5) is a unique 15-deoxy-15,15-difluoro-16-phenoxy prostaglandin F2α (PGF2α) analog used as an efficacious ocular hypotensive agent in the treatment of glaucoma and ocular hypertension, as monotherapy, or as adjunctive therapy to β-blockers. A novel convergent synthesis of 5 was developed employing Julia–Lythgoe olefination of the structurally advanced prostaglandin phenylsulfone 16, also successfully applied for manufacturing of pharmaceutical grade latanoprost (2), travoprost (3) and bimatoprost (4), with an aldehyde ω-chain synthon 17. The use of the same prostaglandin phenylsulfone 16, as a starting material in parallel syntheses of all commercially available antiglaucoma PGF2α analogs 2–5, significantly reduces manufacturing costs resulting from its synthesis on an industrial scale and development of technological documentation. Another key aspect of the route developed is deoxydifluorination of a trans-13,14-en-15-one 30 with Deoxo-Fluor. Subsequent hydrolysis of protecting groups and final esterification of acid 6 yielded tafluprost (5). The main advantages are the preparation of high purity tafluprost (5) and the application of comparatively cheap reagents. The preparation and identification of two other tafluprost acid derivatives, tafluprost methyl ester (32) and tafluprost ethyl amide (33), are also described.","PeriodicalId":19033,"journal":{"name":"Molecules : A Journal of Synthetic Chemistry and Natural Product Chemistry","volume":"12 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80024420","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Transcription Profile Unveils the Cardio-Protective Effect of Aspalathin against Lipid Toxicity in an In Vitro H9c2 Model","authors":"Rabia Johnson, P. Dludla, C. Muller, B. Huisamen, M. Essop, J. Louw","doi":"10.3390/molecules22020219","DOIUrl":"https://doi.org/10.3390/molecules22020219","url":null,"abstract":"Aspalathin, a C-glucosyl dihydrochalcone, has previously been shown to protect cardiomyocytes against hyperglycemia-induced shifts in substrate preference and subsequent apoptosis. However, the precise gene regulatory network remains to be elucidated. To unravel the mechanism and provide insight into this supposition, the direct effect of aspalathin in an isolated cell-based system, without the influence of any variables, was tested using an H9c2 cardiomyocyte model. Cardiomyocytes were exposed to high glucose (33 mM) for 48 h before post-treatment with or without aspalathin. Thereafter, RNA was extracted and RT2 PCR Profiler Arrays were used to profile the expression of 336 genes. Results showed that, 57 genes were differentially regulated in the high glucose or high glucose and aspalathin treated groups. Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) analysis revealed lipid metabolism and molecular transport as the biological processes altered after high glucose treatment, followed by inflammation and apoptosis. Aspalathin was able to modulate key regulators associated with lipid metabolism (Adipoq, Apob, CD36, Cpt1, Pparγ, Srebf1/2, Scd1 and Vldlr), insulin resistance (Igf1, Akt1, Pde3 and Map2k1), inflammation (Il3, Il6, Jak2, Lepr, Socs3, and Tnf13) and apoptosis (Bcl2 and Chuk). Collectively, our results suggest that aspalathin could reverse metabolic abnormalities by activating Adipoq while modulating the expression of Pparγ and Srebf1/2, decreasing inflammation via Il6/Jak2 pathway, which together with an observed increased expression of Bcl2 prevents myocardium apoptosis.","PeriodicalId":19033,"journal":{"name":"Molecules : A Journal of Synthetic Chemistry and Natural Product Chemistry","volume":"102 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88991358","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In Situ Coupling of Ultrasound to Electro- and Photo-Deposition Methods for Materials Synthesis","authors":"A. Magdziarz, J. C. Colmenares","doi":"10.3390/molecules22020216","DOIUrl":"https://doi.org/10.3390/molecules22020216","url":null,"abstract":"This short review provides the current state-of-the-art of in situ coupling of ultrasound to chemical deposition methods. Synergetic action of ultrasound and light radiation or electrical fields may result in new powerful methodologies, which include sonophotodeposition and sonoelectrodeposition processes. The effect of ultrasound is explained on the basis of different physical mechanisms emerging from cavitation phenomenon. Some possible mechanisms of the interactions between ultrasound and photochemical and electrochemical processes are discussed here. The application of sonophotodeposition and sonoelectrodeposition as green energy sources in the syntheses of different nanomaterials is also reviewed.","PeriodicalId":19033,"journal":{"name":"Molecules : A Journal of Synthetic Chemistry and Natural Product Chemistry","volume":"39 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91267195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the Effects of Geographical Origin on the Chemical Composition and Quality Grading of Vitis vinifera L. cv. Chardonnay Grapes","authors":"J. Gambetta, D. Cozzolino, S. Bastian, D. Jeffery","doi":"10.3390/molecules22020218","DOIUrl":"https://doi.org/10.3390/molecules22020218","url":null,"abstract":"The relationship between berry chemical composition, region of origin and quality grade was investigated for Chardonnay grapes sourced from vineyards located in seven South Australian Geographical Indications (GI). Measurements of basic chemical parameters, amino acids, elements, and free and bound volatiles were conducted for grapes collected during 2015 and 2016. Multiple factor analysis (MFA) was used to determine the sets of data that best discriminated each GI and quality grade. Important components for the discrimination of grapes based on GI were 2-phenylethanol, benzyl alcohol and C6 compounds, as well as Cu, Zn, and Mg, titratable acidity (TA), total soluble solids (TSS), and pH. Discriminant analysis (DA) based on MFA results correctly classified 100% of the samples into GI in 2015 and 2016. Classification according to grade was achieved based on the results for elements such as Cu, Na, Fe, volatiles including C6 and aryl alcohols, hydrolytically-released volatiles such as (Z)-linalool oxide and vitispirane, pH, TSS, alanine and proline. Correct classification through DA according to grade was 100% for both vintages. Significant correlations were observed between climate, GI, grade, and berry composition. Climate influenced the synthesis of free and bound volatiles as well as amino acids, sugars, and acids, as a result of higher temperatures and precipitation.","PeriodicalId":19033,"journal":{"name":"Molecules : A Journal of Synthetic Chemistry and Natural Product Chemistry","volume":"25 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87357191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis of 16 New Hybrids from Tetrahydropyrans Derivatives and Morita-Baylis-Hillman Adducts: In Vitro Screening against Leishmania donovani","authors":"Suervy Canuto de Oliveira Sousa, Juliana da Câmara Rocha, Tatjana de Souza Lima Keesen, Everton da Paz Silva, P. A. C. de Assis, J. P. G. de Oliveira, S. L. Capim, F. Xavier, B. Marinho, F. P. Silva, C. Lima‐Junior, M. Vasconcellos","doi":"10.3390/molecules22020207","DOIUrl":"https://doi.org/10.3390/molecules22020207","url":null,"abstract":"Leishmaniases are a group of neglected tropical diseases (NTDs) caused by protozoan parasites from >20 Leishmania species. Visceral leishmaniasis (VL), also known as kala-aza, is the most severe form of leishmaniasis, usually fatal in the absence of treatment in 95% of cases. The Morita-Baylis-Hillman adducts (MBHAs) are being explored as drug candidates against several diseases, one of them being leishmaniasis. We present here the design, synthesis and in vitro screening against Leishmania donovani of sixteen new molecular hybrids from analgesic/anti-inflammatory tetrahydropyrans derivatives and Morita-Baylis-Hillman adducts. First, acrylates were synthesized from analgesic/anti-inflammatory tetrahydropyrans using acrylic acid under TsOH as a catalyst (70%–75% yields). After the 16 new MBHAs were prepared in moderate to good yields (60%–95%) promoted by microwave irradiation or low temperature (0 °C) in protic and aprotic medium. The hybrids were evaluated in vitro on the promastigote stage of Leishmania donovani by determining their inhibitory concentrations 50% (IC50), 50% hemolysis concentration (HC50), selectivity index (HC50/IC50,), and comparing to Amphotericin B, chosen as the anti-leishmanial reference drug. The hybrid which presents the bromine atom in its chemical structure presents high leishmanicide activity and the high selectivity index in red blood cells (SIrb > 180.19), compared with the highly-toxic reference drug (SIrb = 33.05), indicating that the bromine hybrid is a promising compound for further biological studies.","PeriodicalId":19033,"journal":{"name":"Molecules : A Journal of Synthetic Chemistry and Natural Product Chemistry","volume":"47 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91540564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evolution of Complex Target SELEX to Identify Aptamers against Mammalian Cell-Surface Antigens","authors":"Prabodhika R. Mallikaratchy","doi":"10.3390/molecules22020215","DOIUrl":"https://doi.org/10.3390/molecules22020215","url":null,"abstract":"The demand has increased for sophisticated molecular tools with improved detection limits. Such molecules should be simple in structure, yet stable enough for clinical applications. Nucleic acid aptamers (NAAs) represent a class of molecules able to meet this demand. In particular, aptamers, a class of small nucleic acid ligands that are composed of single-stranded modified/unmodified RNA/DNA molecules, can be evolved from a complex library using Systematic Evolution of Ligands by EXponential enrichment (SELEX) against almost any molecule. Since its introduction in 1990, in stages, SELEX technology has itself undergone several modifications, improving selection and broadening the repertoire of targets. This review summarizes these milestones that have pushed the field forward, allowing researchers to generate aptamers that can potentially be applied as therapeutic and diagnostic agents.","PeriodicalId":19033,"journal":{"name":"Molecules : A Journal of Synthetic Chemistry and Natural Product Chemistry","volume":"9 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87526430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetics Studies of 12 Alkaloids in Rat Plasma after Oral Administration of Zuojin and Fan-Zuojin Formulas","authors":"Ping-Ting Qian, You-bo Zhang, Yan-Fang Yang, Wei Xu, Xiu-wei Yang","doi":"10.3390/molecules22020214","DOIUrl":"https://doi.org/10.3390/molecules22020214","url":null,"abstract":"Zuojin formula (ZJ) is a traditional Chinese medicine (TCM) prescription consisted of Coptidis Rhizoma (CR) and Euodiae Fructus (EF), and has been used to treat gastrointestinal (GI) disease for more than 700 years. Fan-Zuojin formula (FZJ) is a related TCM prescription also consisted of CR and EF with the opposite proportion. In recent years, ZJ was getting more attention for its antitumor potential, but the indeterminate pharmacokinetic (PK) behavior restricted its clinical applications, and the PK differences between ZJ and FZJ were also largely unknown. Consequently it is necessary to carry out a full-scale PK study to demonstrate the physiological disposition of ZJ, as well as the comparative PK study between ZJ and FZJ to illustrate the compatibility dose effects. Therefore a liquid chromatographic–tandem mass spectrometry (LC–MS/MS) method was established and validated for the determinations of coptisine, epiberberine, palmatine, berberine, 8-oxocoptisine, 8-oxoepiberberine, noroxyhydrastinine, corydaldine, dehydroevodiamine, evodiamine, wuchuyuamide-I, and evocarpine in rat plasma. PK characteristics of 12 alkaloids after oral administration of ZJ and FZJ were compared, and the result was analyzed and discussed with the help of an in silico study. Then an integrated PK study was carried out with the AUC-based weighting method and the total drug concentration method. The established method has been successfully applied to reveal the PK profiles of the 12 alkaloids in rat plasma after oral administration of ZJ and FZJ. The results showed that: (1) double peaks were observed in the plasma concentration-time (C–T) curves of the alkaloids after ZJ administration; but the C–T curves approximately matched the two-compartment model after FZJ administration; (2) There were wide variations in the absorption levels of these alkaloids; and even for a certain alkaloid, the dose modified systemic exposure levels and elimination rate also varied significantly after administration of ZJ and FZJ extracts. The results could be interpreted as follows: firstly, inhibition effect on GI motility caused by the high content CR alkaloids (especially berberine) in ZJ could delay the Tmax, and increase the absorption and systemic exposure levels of the other alkaloids, and also lead to the double peak phenomenon of these alkaloids. However, for quaternary protoberberine alkaloids (QPA), double peaks were primarily caused by the different Ka value in two intestinal absorption sites; Secondly, absorption was the major obstacle to the systemic exposure level of the alkaloids from CR and EF. In silico and PK studies suggested that the absorption of these alkaloids, except QPAs, mainly depended on their solubility rather than permeability; Thirdly, EF could promote the absorption and accelerate the elimination of QPAs, and had a greater influence on the former than the latter. At last the integrated PK analysis suggested that berberine and dehydroevodiamine could be reg","PeriodicalId":19033,"journal":{"name":"Molecules : A Journal of Synthetic Chemistry and Natural Product Chemistry","volume":"57 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77494807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immobilized Lipases on Functionalized Silica Particles as Potential Biocatalysts for the Synthesis of Fructose Oleate in an Organic Solvent/Water System","authors":"Vinícius Vescovi, R. C. Giordano, A. Mendes, P. Tardioli","doi":"10.3390/molecules22020212","DOIUrl":"https://doi.org/10.3390/molecules22020212","url":null,"abstract":"Lipases from Thermomyces lanuginosus (TLL) and Pseudomonas fluorescens (PFL) were immobilized on functionalized silica particles aiming their use in the synthesis of fructose oleate in a tert-butyl alcohol/water system. Silica particles were chemically modified with octyl (OS), octyl plus glutaraldehyde (OSGlu), octyl plus glyoxyl (OSGlx), and octyl plus epoxy groups (OSEpx). PFL was hyperactivated on all functionalized supports (more than 100% recovered activity) using low protein loading (1 mg/g), however, for TLL, this phenomenon was observed only using octyl-silica (OS). All prepared biocatalysts exhibited high stability by incubating in tert-butyl alcohol (half-lives around 50 h at 65 °C). The biocatalysts prepared using OS and OSGlu as supports showed excellent performance in the synthesis of fructose oleate. High ester synthesis was observed when a small amount of water (1%, v/v) was added to the organic phase, allowing an ester productivity until five times (0.88–0.96 g/L.h) higher than in the absence of water (0.18–0.34 g/L.h) under fixed enzyme concentration (0.51 IU/g of solvent). Maximum ester productivity (16.1–18.1 g/L.h) was achieved for 30 min of reaction catalyzed by immobilized lipases on OS and OSGlu at 8.4 IU/mL of solvent. Operational stability tests showed satisfactory stability after four consecutive cycles of reaction.","PeriodicalId":19033,"journal":{"name":"Molecules : A Journal of Synthetic Chemistry and Natural Product Chemistry","volume":"26 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82817992","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Application of the Crystalline Sponge Method to Revise the Structure of the Phenalenone Fuliginone","authors":"R. Brkljača, B. Schneider, W. Hidalgo, Felipe Otálvaro, Felipe Ospina, Shoukou Lee, M. Hoshino, M. Fujita, S. Urban","doi":"10.3390/molecules22020211","DOIUrl":"https://doi.org/10.3390/molecules22020211","url":null,"abstract":"The structure of fuliginone was revised from a phenyl substituted phenalenone to a hydroxyl substituted phenalenone as a result of its re-purification via HPLC with subsequent NMR analysis together with an independent synthesis and analysis of the crystal structure, which was secured via the crystalline sponge method. On-flow High Performance Liquid Chromatography coupled to Nuclear Magnetic Resonance spectroscopy (HPLC-NMR) was employed to confirm the presence of the natural product in the plant extract and to monitor for any possible degradation or conversion of the compound.","PeriodicalId":19033,"journal":{"name":"Molecules : A Journal of Synthetic Chemistry and Natural Product Chemistry","volume":"92 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80411034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of Quinone Reductase 2 in the Antimalarial Properties of Indolone-Type Derivatives","authors":"Laure-Estelle Cassagnes, Nambinina V. Rakotoarivelo, S. Sirigu, P. Pério, Ennaji Najahi, L. Chavas, A. Thompson, R. Gayon, G. Ferry, J. Boutin, A. Valentin, K. Reybier, F. Nepveu","doi":"10.3390/molecules22020210","DOIUrl":"https://doi.org/10.3390/molecules22020210","url":null,"abstract":"Indolone-N-oxides have antiplasmodial properties against Plasmodium falciparum at the erythrocytic stage, with IC50 values in the nanomolar range. The mechanism of action of indolone derivatives involves the production of free radicals, which follows their bioreduction by an unknown mechanism. In this study, we hypothesized that human quinone reductase 2 (hQR2), known to act as a flavin redox switch upon binding to the broadly used antimalarial chloroquine, could be involved in the activity of the redox-active indolone derivatives. Therefore, we investigated the role of hQR2 in the reduction of indolone derivatives. We analyzed the interaction between hQR2 and several indolone-type derivatives by examining enzymatic kinetics, the substrate/protein complex structure with X-ray diffraction analysis, and the production of free radicals with electron paramagnetic resonance. The reduction of each compound in cells overexpressing hQR2 was compared to its reduction in naïve cells. This process could be inhibited by the specific hQR2 inhibitor, S29434. These results confirmed that the anti-malarial activity of indolone-type derivatives was linked to their ability to serve as hQR2 substrates and not as hQR2 inhibitors as reported for chloroquine, leading to the possibility that substrate of hQR2 could be considered as a new avenue for the design of new antimalarial compounds.","PeriodicalId":19033,"journal":{"name":"Molecules : A Journal of Synthetic Chemistry and Natural Product Chemistry","volume":"22 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87312282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}