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Mechanistic Rationale (mechanistic + rationale)
Selected AbstractsA Mechanistic Rationale for the Mode Selectivity in the Intramolecular Cyclization of Ethylene-Tethered Iminoketenimines: [2+2] versus [4+2] Stepwise CycloadditionsEUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 12 2004Mateo Alajarín Abstract A stepwise mechanism, via a zwitterionic intermediate, has been established by ab initio and DFT calculations for the intramolecular cyclization of N -(3-azabut-3-enyl)ketenimine into its corresponding [2+2] cycloadduct. The control of the mode selectivity ([2+2] versus [4+2] cycloaddition) in the intramolecular cyclization of C -vinyl- N -(iminoethylene)ketenimines, which favors the [4+2] cycloadducts, also has been rationalized by comparing the energies calculated for both reaction pathways; the results have been confirmed by a quantitative kinetic analysis. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004) [source] A Coherent Mechanistic Rationale for Additive Effects and Autoinductive Behaviour in Proline-Mediated ReactionsADVANCED SYNTHESIS & CATALYSIS (PREVIOUSLY: JOURNAL FUER PRAKTISCHE CHEMIE), Issue 17 2009Natalia Zotova Abstract Differences in the kinetic behaviour of aldol reactions compared to aminoxylation and amination reactions are rationalized by consideration of the rate-determining step in each case. Both autoinductive behaviour and the rate-enhancing effect of additives are attributed to an effect on the enamine formation step. [source] Defining the roles of T cell membrane proteinase and CD44 in type 1 diabetesIUBMB LIFE, Issue 1 2007Alexei Y. Savinov Abstract Membrane type-1 matrix metalloproteinase (MT1-MMP) shedding of the signaling and adhesion CD44 receptor plays a significant role in stimulating cancer cells locomotion. Similarly, and unexpectedly, MT1-MMP-dependent shedding of CD44 plays an equally significant role in regulating the adhesion to the pancreatic vasculature and also in the concomitant transendothelial migration and intra-islet homing of the diabetogenic, cytotoxic, T cells. Inactivation of the T cell MT1-MMP functionality by clinically tested, synthetic inhibitors leads to an extended immobilization of the T killer cells on the pancreatic vasculature and, subsequently, to immunosuppression because of the cessation of the T cell transmigration and homing. Injections of insulin jointly with an MT1-MMP inhibitor stimulated the regeneration of functional, insulin-producing, ,-cells in acutely diseased non-obese diabetic (NOD) mice. After insulin injections were suspended and inhibitor injections continued, diabetic NOD mice maintained mild hyperglycemia and did not require further insulin injections for survival. Overall, these data provide a substantive mechanistic rationale for clinical trials of the inhibitors of MT1-MMP in human type 1 diabetes. IUBMB Life, 59: 6-13, 2007 [source] Curcumin-induced apoptosis in ovarian carcinoma cells is p53-independent and involves p38 mitogen-activated protein kinase activation and downregulation of Bcl-2 and survivin expression and Akt signaling,MOLECULAR CARCINOGENESIS, Issue 1 2010Jane L. Watson Abstract New cytotoxic agents are urgently needed for the treatment of advanced ovarian cancer because of the poor long-term response of this disease to conventional chemotherapy. Curcumin, obtained from the rhizome of Curcuma longa, has potent anticancer activity; however, the mechanism of curcumin-induced cytotoxicity in ovarian cancer cells remains a mystery. In this study we show that curcumin exhibited time- and dose-dependent cytotoxicity against monolayer cultures of ovarian carcinoma cell lines with differing p53 status (wild-type p53: HEY, OVCA429; mutant p53: OCC1; null p53: SKOV3). In addition, p53 knockdown or p53 inhibition did not diminish curcumin killing of HEY cells, confirming p53-independent cytotoxicity. Curcumin also killed OVCA429, and SKOV3 cells grown as multicellular spheroids. Nuclear condensation and fragmentation, as well as DNA fragmentation and poly (ADP-ribose) polymerase-1 cleavage in curcumin-treated HEY cells, indicated cell death by apoptosis. Procaspase-3, procaspase-8, and procaspase-9 cleavage, in addition to cytochrome c release and Bid cleavage into truncated Bid, revealed that curcumin activated both the extrinsic and intrinsic pathways of apoptosis. Bax expression was unchanged but Bcl-2, survivin, phosphorylated Akt (on serine 473), and total Akt were downregulated in curcumin-treated HEY cells. Curcumin also activated p38 mitogen-activated protein kinase (MAPK) without altering extracellular signal-regulated kinase 1/2 activity. We conclude that p53-independent curcumin-induced apoptosis in ovarian carcinoma cells involves p38 MAPK activation, ablation of prosurvival Akt signaling, and reduced expression of the antiapoptotic proteins Bcl-2 and survivin. These data provide a mechanistic rationale for the potential use of curcumin in the treatment of ovarian cancer. © 2009 Wiley-Liss, Inc. [source] In vivo Mutational Analysis of the Mupirocin Gene Cluster Reveals Labile Points in the Biosynthetic Pathway: the "Leaky Hosepipe" MechanismCHEMBIOCHEM, Issue 9 2008Ji'en Wu Dr. Abstract A common feature of the mupirocin and other gene clusters of the AT-less polyketide synthase (PKS) family of metabolites is the introduction of carbon branches by a gene cassette that contains a ,-hydroxy-,-methylglutaryl CoA synthase (HMC) homologue and acyl carrier protein (ACP), ketosynthase (KS) and two crotonase superfamily homologues. In vivo studies of Pseudomonas fluorescens strains in which any of these components have been mutated reveal a common phenotype in which the two major isolable metabolites are the truncated hexaketide mupirocin H and the tetraketide mupiric acid. The structure of the latter has been confirmed by stereoselective synthesis. Mupiric acid is also the major metabolite arising from inactivation of the ketoreductase (KR) domain of module 4 of the modular PKS. A number of other mutations in the tailoring region of the mupirocin gene cluster also result in production of both mupirocin H and mupiric acid. To explain this common phenotype we propose a mechanistic rationale in which both mupirocin H and mupiric acid represent the products of selective and spontaneous release from labile points in the pathway that occur at significant levels when mutations block the pathway either close to or distant from the labile points. [source] Bifunctional Catalysis by Natural Cinchona Alkaloids: A Mechanism ExplainedCHEMISTRY - A EUROPEAN JOURNAL, Issue 32 2009Clotilde Abstract The use of bifunctional chiral catalysts, which are able to simultaneously bind and activate two reacting partners, currently represents an efficient and reliable strategy for the stereoselective preparation of valuable chiral compounds. Cinchona alkaloids such as quinine and quinidine, simple organic molecules generously provided by Nature, were the first compounds to be proposed to operate through a cooperative catalysis. To date, a full mechanistic characterization of the dual catalysis mode of cinchona alkaloids has proven a challenging objective, due to the transient, non-covalent nature of the involved catalyst,substrate interactions. Here, we propose a mechanistic rationale on how natural cinchona alkaloids act as efficient bifunctional catalysts by using a broad range of computational methods, including classical molecular dynamics, a mixed quantum mechanical/molecular mechanics (QM/MM) approach, and correlated ab-initio calculations. We also unravel the origin of enantio- and diastereoselectivity, which is due to a specific network of hydrogen bonds that stabilize the transition state of the rate-determining step. The results are validated by experimental evidence. [source] Unique Reactivity of the Mukaiyama Glycosidation Catalyst (SnCl3ClO4) Toward ,-MannopyranosidesCHEMISTRY - AN ASIAN JOURNAL, Issue 2 2008Yonghui Wang Dr. Abstract Glycosidation of a mannosyl donor in the presence of the Mukaiyama catalyst was found to give exceptionally high ,/, selectivity. A systematic study was conducted to reveal that selective ,-to-, anomerization accounts for the observed high ,/, stereoselectivity. Furthermore, the Mukaiyama catalyst was shown to exhibit an unusual level of substrate and anomer selectivity for the anomerization. On the basis of the combined anomeric and ,2 effects, a mechanistic rationale was proposed, thereby suggesting the minimum structural moiety essential for the anomerization in question. With this analysis, ,-talo-, ,-altro-, and ,-idopyranosides are predicted to exhibit a reactivity profile similar to ,-mannopyranosides, but all other pyranosides should not. This prediction was verified by using ,- and ,-talopyranosides as an example. [source] | |||||||||||||||||||