Kinetic Resolution of Racemic 2‑Hydroxy-γ-butyrolactones by Asymmetric Esterification Using Diphenylacetic Acid with Pivalic Anhydride and a Chiral Acyl-Transfer Catalyst

Various optically active 2-hydroxy-γ-butyrolactone derivatives are produced via the kinetic resolution of racemic 2-hydroxy-γ-butyrolactones with diphenylacetic acid using pivalic anhydride and (<i>R</i>)-benzotetramisole ((<i>R</i>)-BTM), a chiral acyl-transfer catalyst. Importantly, the substrate scope of this novel protocol is fairly broad (12 examples, <i>s</i>-value; up to over 1000). In addition, we succeeded in disclosing the reaction mechanism to afford high enantioselectivity using theoretical calculations and expounded on the substituent effects at the C-3 positions in 2-hydroxylactones

Total Synthesis and Antimicrobial Activities of All Stereoisomers of (16<i>Z</i>,20<i>E</i>)‑Eushearilide and (16<i>E</i>,20<i>E</i>)‑Eushearilide

As promising antifungal agents, the eight stereoisomers of eushearilide, including the natural compound, were synthesized relying on an asymmetric Mukaiyama aldol reaction, Julia–Kocienski olefination, and Shiina macrolactonization. Moreover, their <i>in vitro</i> antimicrobial activities against some fungi and bacteria were evaluated by the disk-diffusion method, which revealed that not only natural eushearilide but also its stereoisomers exhibited significant antimicrobial activity against a variety of fungi and bacteria

The budgetary-monetary price regulation in the transformation economy

Визначено сутність, функції та структуру механізму бюджетно-монетарного регулювання цін. Обгрунтовано, що в процесі ринкової трансформації економіки відбувається об’єктивна заміна прямих адміністративних інструментів цінорегулювання непрямими економічними, серед яких зростає роль податково-бюджетних, видатково-бюджетних і грошово-кредитних регуляторів. Визначено особливості впливу прямих, непрямих податків і субсидій на рівень, структуру і динаміку цін. Установлено особливості функціонального зв’язку між динамікою цін та грошових агрегатів і запропоновано механізм досягнення макроекономічної цінової стабільності монетарними інструментами.The essence, functions and the structure of the mechanism of the budgetary-monetary price regulation are determined. It is proved, that during the market transformation of economy there is an objective replacement of direct administrative tools of price regulation for indirect economic tools, among which the role of tax-budgetary, expenditure-budgetary and monetary regulators grows. Features of influence of straight lines, indirect taxes and grants on the level, structure and dynamics of prices are determined. Features of functional relations between dynamics of the general price level and monetary aggregates are established and the mechanism of the achievement of macroeconomic price stability is offered with tools of monetary regulation

MNBA-Mediated β-Lactone Formation: Mechanistic Studies and Application for the Asymmetric Total Synthesis of Tetrahydrolipstatin

Various β-lactones were prepared from β-hydroxycarboxylic acids by intramolecular dehydration condensation using MNBA, an effective coupling reagent, along with a nucleophilic catalyst. The transition state that provides the desired 4-membered ring model system is disclosed by density functional theory (DFT) calculations, and the structural features of the transition form are discussed. This method was successfully applied to the asymmetric total synthesis of tetrahydrolipstatin (THL), an antiobestic drug used in clinical treatment to inhibit the activity of pancreatic lipase

M-COPA suppresses endolysosomal Kit-Akt oncogenic signalling through inhibiting the secretory pathway in neoplastic mast cells

<div><p>Gain-of-function mutations in Kit receptor tyrosine kinase result in the development of a variety of cancers, such as mast cell tumours, gastrointestinal stromal tumours (GISTs), acute myeloid leukemia, and melanomas. The drug imatinib, a selective inhibitor of Kit, is used for treatment of mutant Kit-positive cancers. However, mutations in the Kit kinase domain, which are frequently found in neoplastic mast cells, confer an imatinib resistance, and cancers expressing the mutants can proliferate in the presence of imatinib. Recently, we showed that in neoplastic mast cells that endogenously express an imatinib-resistant Kit mutant, Kit causes oncogenic activation of the phosphatidylinositol 3-kinase-Akt (PI3K-Akt) pathway and the signal transducer and activator of transcription 5 (STAT5) but only on endolysosomes and on the endoplasmic reticulum (ER), respectively. Here, we show a strategy for inhibition of the Kit-PI3K-Akt pathway in neoplastic mast cells by M-COPA (2-methylcoprophilinamide), an inhibitor of this secretory pathway. In M-COPA-treated cells, Kit localization in the ER is significantly increased, whereas endolysosomal Kit disappears, indicating that M-COPA blocks the biosynthetic transport of Kit from the ER. The drug greatly inhibits oncogenic Akt activation without affecting the association of Kit with PI3K, indicating that ER-localized Kit-PI3K complex is unable to activate Akt. Importantly, M-COPA but not imatinib suppresses neoplastic mast cell proliferation through inhibiting anti-apoptotic Akt activation. Results of our M-COPA treatment assay show that Kit can activate Erk not only on the ER but also on other compartments. Furthermore, Tyr568/570, Tyr703, Tyr721, and Tyr936 in Kit are phosphorylated on the ER, indicating that these five tyrosine residues are all phosphorylated before mutant Kit reaches the plasma membrane (PM). Our study provides evidence that Kit is tyrosine-phosphorylated soon after synthesis on the ER but is unable to activate Akt and also demonstrates that M-COPA is efficacious for growth suppression of neoplastic mast cells.</p></div