Dimethyl sulfoxide (DMSO) has been known to enhance cell membrane permeability of drugs or DNA. Molecular dynamics (MD) simulations with single-component lipid bilayers predicted the existence of three regimes of action of DMSO: membrane loosening, pore formation and bilayer collapse. We show here that these modes of action are also reproduced in the presence of cholesterol in the bilayer, and we provide a description at the atomic detail of the DMSO-mediated process of pore formation in cholesterol-containing lipid membranes. We also successfully explore the applicability of DMSO to promote plasma membrane permeability to water, calcium ions (Ca2+) and Yo-Pro-1 iodide (Yo-Pro-1) in living cell membranes. The experimental results on cells in culture can be easily explained according to the three expected regimes: in the presence of low doses of DMSO, the membrane of the cells exhibits undulations but no permeability increase can be detected, while at intermediate DMSO concentrations cells are permeabilized to water and calcium but not to larger molecules as Yo-Pro-1. These two behaviors can be associated to the MD-predicted consequences of the effects of the DMSO at low and intermediate DMSO concentrations. At larger DMSO concentrations, permeabilization is larger, as even Yo-Pro-1 can enter the cells as predicted by the DMSO-induced membrane-destructuring effects described in the MD simulations.
[formula: see text] A catalytic method for the enantioselective ring opening of meso aziridines by TMSN3 is described. Tridentate Schiff base chromium complexes derived from 1-amino-2-indanol were identified as the optimal catalysts.
We present a numerical study of pore formation in lipid bilayers containing cholesterol (Chol) and subjected to a transverse electric field. Molecular dynamics simulations of 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DOPC) membranes reveal the formation of a pore when an electric field of 325 mV/nm is applied. The minimum electric field needed for membrane permeabilization strongly increases with the addition of cholesterol above 10 mol %, reaching 750 mV/nm for 40 mol % Chol. Analysis of simulations of DOPC/Chol bilayers suggests this is caused by a substantial increment of membrane cohesion. Simulations also show that pore formation kinetics is much slower at high Chol contents.
2-Methyl-I ,3-dimorpholino-l,3-butadiene 1 reacted with a,a-unsaturated Fischer carbene complexes to give a wide range of different products depending on the substitution pattern. Thus, sevenmembcred rings (4, 5 and 6) could be obtained from chromium complexes 2 with aromatic or vinylic groups at the /I position. Similar results were observed when a-methyl-substituted carbene complex 7 a was used. Six-membered carbocycles (derivatives of cycloadducts 12 and 13) were isolated after reaction with both chromium and tungsten complexes bearing one or two alkyl groups at the /3 position (10 and 11). Moreover, cyclopentenones 20 were the main products when the starting carbene complexes were alkylsubstituted at both CI and /3 positions (19a, b) or when aromatic (19c,d) instead of vinylic complexes were used. A bicy-
A novel approach for the synthesis of the important indole ring is described. Indoles are obtained from o-bromoanilines and alkenyl halides in a Pd-catalyzed cascade process that involves an alkenyl amination followed by an intramolecular Heck reaction. The overall process represents the first example of the participation of alkenyl amination reactions in Pd-catalyzed cascade reactions. Initially, the relative reactivity of aryl and alkenyl bromides and chlorides towards Pd-catalyzed amination was investigated. Competition experiments were carried out in the presence of primary and secondary amines, and these revealed the reactivity order alkenyl bromides > aryl bromides > alkenyl chlorides > aryl chlorides, as well as very high chemoselectivity; the more reactive halide was always favored. Thereafter, optimized reaction conditions for the sequential alkenyl amination/Heck cyclization to give indoles were investigated with the model reaction of o-bromoaniline with alpha-bromostyrene. An extensive screening of ligands, bases, and reaction conditions revealed that the [Pd2(dba)3]/DavePhos, NaOtBu, toluene combination at 100 degrees C were the optimized reaction conditions to carry out the cascade process (dba=dibenzylideneacetone, DavePhos=2-dicyclohexylphosphino-2'-N,N-dimethylaminobiphenyl). The reaction proceeds with aryl, alkyl, and functionalized substitutents in both starting reactants. The cyclization was also studied with N-substituted o-bromoanilines (which would give rise to N-substituted indoles); however, in this case, indole formation occurred only with 1-substituted-2-bromoalkenes. Finally, the application of this methodology to o-chloroanilines required further optimization. Although the catalyst based on DavePhos failed to promote the cascade process, a catalytic combination based on [Pd2(dba)3]/X-Phos promoted the formation of the indole ring also from the less reactive chloroanilines.
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