In this paper, we report the synthesis of spirocyclopropane-containing 4H-pyrazolo1,5-aindoles 6a–e via alkylative dearomatization and intramolecular N-imination of indole–O-(methylsulfonyl)oxime 11. ...Starting materials tryptophol (7) and 2-bromocyclopetanone (8) were reacted in the presence of HBFsub.4·OEtsub.2, providing 1,2,3,5,6,11-hexahydrocyclopenta2,3oxepino4,5-bindole (9) in a 63% yield. Compound 9 was reacted with hydroxylamine hydrochloride to afford oxime 10 (65% yield), which was subsequently bis-methanesulfonated to form 11 in a 85% yield. Heating 11 with various alcohols in the presence of N,N-diisopropylethylamine (DIPEA) triggered the alkylative dearomatization and intramolecular N-imination, forming the spirocyclopropane and 4H-pyrazolo1,5-aindole structures in the targets 6a–e with 67–84% yields.
CACNA1C encodes the pore-forming α1C subunit of the L-type Casup.2+ channel, Cav1.2. Mutations and polymorphisms of the gene are associated with neuropsychiatric and cardiac disease. ...Haploinsufficient Cacna1c+/− rats represent a recently developed model with a behavioral phenotype, but its cardiac phenotype is unknown. Here, we unraveled the cardiac phenotype of Cacna1c+/− rats with a main focus on cellular Casup.2+ handling mechanisms. Under basal conditions, isolated ventricular Cacna1c+/− myocytes exhibited unaltered L-type Casup.2+ current, Casup.2+ transients (CaTs), sarcoplasmic reticulum (SR) Casup.2+ load, fractional release, and sarcomere shortenings. However, immunoblotting of left ventricular (LV) tissue revealed reduced expression of Cav1.2, increased expression of SERCA2a and NCX, and augmented phosphorylation of RyR2 (at S2808) in Cacna1c+/− rats. The β-adrenergic agonist isoprenaline increased amplitude and accelerated decay of CaTs and sarcomere shortenings in both Cacna1c+/− and WT myocytes. However, the isoprenaline effect on CaT amplitude and fractional shortening (but not CaT decay) was impaired in Cacna1c+/− myocytes exhibiting both reduced potency and efficacy. Moreover, sarcolemmal Casup.2+ influx and fractional SR Casup.2+ release after treatment with isoprenaline were smaller in Cacna1c+/− than in WT myocytes. In Langendorff-perfused hearts, the isoprenaline-induced increase in RyR2 phosphorylation at S2808 and S2814 was attenuated in Cacna1c+/− compared to WT hearts. Despite unaltered CaTs and sarcomere shortenings, Cacna1c+/− myocytes display remodeling of Casup.2+ handling proteins under basal conditions. Mimicking sympathetic stress with isoprenaline unmasks an impaired ability to stimulate Casup.2+ influx, SR Casup.2+ release, and CaTs caused, in part, by reduced phosphorylation reserve of RyR2 in Cacna1c+/− cardiomyocytes.
A regioselective one-pot method for the synthesis of 1-ethyl 2,4-dihydrochromene3,4-cpyrroles in 63-94% yields from available 2-phenyl-, 2-trifluoro(trichloro)methyl- or ...2-phenyl-2-(trifluoromethyl)-3-nitro-2H-chromenes and ethyl isocyanoacetate through the Barton-Zard reaction in ethanol at reflux for 0.5 h, using Ksub.2COsub.3 as a base, has been developed.
Fusarium basal rot of onions causes large losses during storage of commercial production of onion bulbs, which in turn adversely affects the food market situation in the off-season period. There are ...no data on the composition of Fusarium spp., which causes onion basal rot in the Russian Federation. Therefore, our research was aimed at Fusarium spp. causing onion basal rot in the Moscow Region of the Russian Federation and studying the pathogenicity of these species for the host plant. We studied 20 isolates of Fusarium spp. collected from affected mature bulbs and seed bulbs. Species identification of the isolates was carried out using analysis of the nucleotide sequences of the three genetic loci ITS, tef1 and rpb2, as well as was based on the macro- and micromorphological characteristics of these isolates. As a result, the species F. annulatum (F. fujikuroi species complex), F. oxysporum (F. oxysporum species complex), F. acuminatum (F. tricinctum species complex) and F. solani (F. solani species complex) were identified to involve in the pathogenesis of Fusarium basal rot. We have shown for the first time that the species F. annulatum and F. acuminatum are highly aggressive and capable of causing onion basal rot. The predominant species were F. annulatum and F. oxysporum. The proportion of these species in the total number of analyzed isolates was 60% and 25%, respectively. The largest proportion (33%) of highly aggressive on mature bulbs isolates was found in the species F. annulatum. The data obtained provide practical insights for developing strategies to manage Fusarium fungi responsible for onion basal rot Moscow Region of the Russian Federation. In addition, data about species composition and aggressive isolates may be used in onion breeding for resistance to Fusarium basal rot.
A series of new 3-(indol-3-yl)-4-(pyrazolo3,4-cpyridazin-3-yl)-maleimides were synthesized and evaluated for their inhibitory activity against IDH1-R132H. Most compounds exhibited significant potency ...to IDH1-R132H inhibition. Among these, 3-(1-(3-(1H-imidazol-1-yl)propyl)-6-bromo-1H-indol-3-yl)-4-(1-methyl-1H-pyrazolo3,4-cpyridazin-3-yl)-1H-pyrrole-2,5-dione (compound IXb), was the most promising IDH1-R132H inhibitor (IC.sub.50 = 0.031 muM) and could significantly inhibit the production of 2-HG in U87MG IDH1-R132H cells. Preliminary structure-activity relationships and molecular modeling studies are discussed based on the experimental data obtained.
A polyphenol-rich diet protects against chronic pathologies by modulating numerous physiological processes, such as cellular redox potential, enzymatic activity, cell proliferation and signaling ...transduction pathways. However, polyphenols have a low oral bioavailability mainly due to an extensive biotransformation mediated by phase I and phase II reactions in enterocytes and liver but also by gut microbiota. Despite low oral bioavailability, most polyphenols proved significant biological effects which brought into attention the low bioavailability/high bioactivity paradox. In recent years, polyphenol metabolites have attracted great interest as many of them showed similar or higher intrinsic biological effects in comparison to the parent compounds. There is a huge body of literature reporting on the biological functions of polyphenol metabolites generated by phase I and phase II metabolic reactions and gut microbiota-mediated biotransformation. In this respect, the review highlights the pharmacokinetic fate of the major dietary polyphenols (resveratrol, curcumin, quercetin, rutin, genistein, daidzein, ellagitannins, proanthocyanidins) in order to further address the efficacy of biometabolites as compared to parent molecules. The present work strongly supports the contribution of metabolites to the health benefits of polyphenols, thus offering a better perspective in understanding the role played by dietary polyphenols in human health.
