Two cleavable cationic lipids were designed to trigger the fusogenicity and membrane permeation of their lipoplexes in endosomes via the formation of inverted hexagonal phases (HII). Both lipids contain a cationic head group and an unsaturated hydrophobic dioleylglycerol moiety joined together by a linear or a cyclic ortho ester linker. At pH 7.4, the lipids formed stable complexes with plasmid DNA together with the conelike helper lipid 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE). The decrease of pH enhanced the hydrolysis of the ortho ester linkers, which removed the cationic head groups and caused the aggregation of the lipoplexes. At pH 5.5, the cationic lipid N-[2-methyl-2-(1',2'-dioleylglyceroxy)dioxolan-4-yl]methyl-N,N,N-trimethylammonium iodide (2) with a cyclic ortho ester linker showed exceptional pH-sensitivity and triggered its lipoplex to permeate model biomembranes within the time span of endosome processing prior to lysosomal degradation. Lipid 2 significantly improved gene transfection in cultured cells compared to the pH-insensitive control lipid 1,2-dioleoyl-3-trimethylammoniopropane (DOTAP).
A mechanistic study of chloroboron subphthalocyanine (SubPc) formation from phthalonitrile and BCl 3 in aromatic solvents such as p-xylene or toluene suggests that rearrangement of the initial phthalonitrile- BCl 3 adduct produces (1 Z )-3-chloro-N-(dichloroboryl)-1 H -isoindol-1-imine 3, following rearrangement of the initial phthalonitrile- BCl 3 adduct. From three molecules of (1 Z )-3-chloro-N-(dichloroboryl)-1 H -isoindol-1-imine 3, by successive addition, the dichlorosubstituted macrocycle 7 is formed. Quantum-chemical computation shows that the postulated elementary reaction steps leading up to the formation of the SubPc-precursor macrocycle are indeed exothermic, or at least kinetically allowed. The formation of the SubPc is concluded by the elimination of chlorine which is probably catalyzed by BCl 3 in a concerted process which might be represented as: dichlorosubstituted macrocycle 7 + BCl 3 → SubPc · Cl + + BCl 4- → SubPc + Cl 2 + BCl 3. The chlorine formed may be photolytically affected if the reaction is carried out under ordinary laboratory lighting (fluorescent lamps), giving rise to a free-radical chain reaction involving the solvent. Alternatively, molecular chlorine may react with aromatic solvents such as toluene and p-xylene in a Friedel-Crafts-type reaction catalyzed by BCl 3. In this way, such solvents which are reactive in both ways can protect the reactant phthalonitrile, the reaction intermediates, and the product SubPc from degradation by chlorination.
Molecular dynamics (MD) simulations are well positioned to elucidate the aspects of electrospray ionization (ESI) and high-energy collision dissociation (HCD), as well as give insight into processes that involve neutral species that cannot be observed experimentally in ESI, HCD, and collisioninduced dissociation (CID). Here, we utilize temperature dissociation molecular dynamics (TDMD) to model the HCD/CID of lithium formate clusters carrying a single positive charge. These simulations successfully reproduce the experimental ESI HCD spectra of lithium formate solutions and also support the existence of magic number clusters (MNCs) that have been observed. The simulations also provide strong evidence that the main fragmentation channel of such clusters involves neutral (LiHCOO) 2 dimers.
This study is focused on the final stage of the formation mechanism of chloroboron subphthalocyanine from boron trichloride and phthalonitrile, in the context of recent work on the earlier stages of this reaction. The results of extensive quantum-chemical energetic, structural, and charge-distribution computations show that a catalytic effect of boron trichloride is most probably essential to explain the fact that molecular chlorine is liberated in the formation of chloroboron subphthalocyanine (reaction 2). This process turns out to be closely concerted (reactions 2a and 2b).
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