Encapsulation of Mithramycin in Liposomes in Response to a Transmembrane Gradient of Calcium Ions

The recent discovery that mithramycin(MTR) in aqueous solution forms a high affinity[Ca(MTR)4]2- complex led us to the idea thatCa2+-loaded liposomes might be able to accumulateMTR in their aqueous internal compartment. Wetherefore investigated the uptake of MTR into largeunilamellar vesicles (LUV) containing NaCl orCaCl2. Our data show that MTR was efficientlyaccumulated within LUV made fromdipalmitoylphosphatidylcholine and cholesterol, onlywhen the liposomes contained Ca2+ and wereresuspended in a Ca2+-free medium. A drugencapsulation efficiency as high as 60% was achieved,at a drug to lipid molar ratio of 1/18. The circulardichroism and fluorescence excitation spectra ofliposome-encapsulated MTR (LMTR) displayed strongsimilarities with those of the [Ca(MTR)4]2-complex. LMTR was found to be stable, when submittedto conditions that destabilized the[Ca(MTR)4]2- complex. Upon dilution andincubation for 24 h at 37 °C, MTR-containingliposomes did not release a significant amount of MTR.These properties were attributed to the formation ofa high affinity complex between MTR and Ca2+inthe aqueous compartment of liposomes.     

Room Temperature Ionic Liquids in Asymmetric Hetero-Ene Type Reactions: Improving Organocatalyst Performance at Lower Temperatures

Room temperature ionic liquids (RTILs) have been widely used as (co)solvents in several catalytic processes modifying, in most of the cases, the catalyst activity and/or the selectivity for the studied reactions. However, there are just a few examples of their use in hydrogen bonding organocatalysis. In this paper, we show the positive effect of a set of imidazole-based ionic liquids ([bmim]BF₄ and [hmim]PF₆) in the enantioselective addition of formaldehyde tert-butylhydrazone to prochiral α-keto esters catalyzed by a sugar-based chiral thiourea. Reactions performed in the presence of low percentages of RTILs led to an increase of the catalyst activity, thereby making possible to work at lower temperatures. Thus, the chiral tert-butyl azomethyl tertiary alcohols could be obtained with moderate to good conversions and higher enantioselectivities for most of the studied substrates when using up to 30 vol% of [hmim]PF₆ as a cosolvent in processes performed in toluene.     

Ketone–Alcohol Hydrogen‐Transfer Equilibria: Is the Biooxidation of Halohydrins Blocked?

To ensure the quasi‐irreversibility of the oxidation of alcohols coupled with the reduction of ketones in a hydrogen‐transfer (HT) fashion, stoichiometric amounts of α‐halo carbonyl compounds have been employed as hydrogen acceptors. The reason that these substrates lead to quasi‐quantitative conversions has been tacitly attributed to both thermodynamic and kinetic effects. To provide a clear rationale for this behavior, we investigate herein the redox equilibrium of a selected series of ketones and 2‐propanol by undertaking a study that combines experimental and theoretical approaches. First, the activity of the (R)‐specific alcohol dehydrogenase from Lactobacillus brevis (LBADH) with these substrates was studied. The docking of acetophenone/(R)‐1‐phenyethanol and α‐chloroacetophenone/(S)‐2‐chloro‐1‐phenylethanol in the active site of the enzyme confirms that there seems to be no structural reason for the lack of reactivity of halohydrins. This assumption is confirmed by the fact that the corresponding aluminum‐catalyzed Meerwein–Ponndorf–Verley–Oppenauer (MPVO) reactions afford similar conversions to those obtained with LBADH, showing that the observed reactivity is independent of the catalyst employed. While the initial rates of the enzymatic reductions and the IR ν(C?O) values contradict the general belief that electron‐withdrawing groups increase the electrophilicity of the carbonyl group, the calculated ΔG values of the isodesmic redox transformations of these series of ketones/alcohols with 2‐propanol/acetone support the thermodynamic control of the reaction. As a result, a general method to predict the degree of conversion obtained in the HT‐reduction process of a given ketone based on the IR absorption band of the carbonyl group is proposed, and a strategy to achieve the HT oxidation of halohydrins is also shown.     

Oligopeptides and copeptides of homochiral sequence, via beta-sheets, from mixtures of racemic alpha-amino acids, in a one-pot reaction in water; relevance to biochirogenesis

As part of our studies on the biochirogenesis of peptides of homochiral sequence during early evolution, the formation of oligopeptides composed of 14-24 residues of the same handedness in the polymerization of dl-leucine (Leu), dl-phenylalanine (Phe), and dl-valine (Val) in aqueous solutions, by activation with N, N'-carbonyldiimidazole and then initiation with a primary amine, in a one-pot reaction, was demonstrated by MALDI-TOF MS using deuterium enantio-labeled alpha-amino acids. The formation of long isotactic peptides is rationalized by the following steps occurring in tandem: (i) creation of a library of short diasteroisomeric oligopeptides containing isotactic peptides in excess in comparison to a binomial kinetics, as a result of an asymmetric induction exerted by the N-terminal residue of a given handedness; (ii) precipitation of the less soluble racemic isotactic penta- and hexapeptides in the form of beta-sheets that are delineated by homochiral rims; (iii) regio-enantiospecific chain elongation occurring heterogeneously at the beta-sheets/solution interface. Polymerization of l-Leu with l-isoleucine (Ile) or l-Phe with l- (1) N-Me-histidine yielded mixtures of copeptides containing both residues. In contrast, in the polymerization of the corresponding mixtures of l- + d-alpha-amino acids, the long oligopeptides were composed mainly from oligo- l-Leu and oligo- d-Ile in the first system and oligo- d-Phe in the second. Furthermore, in the polymerization of mixtures of hydrophobic racemic alpha-amino acids dl-Leu, dl-Val, and dl-Phe and with added racemic dl-alanine and dl-tyrosine, copeptides of homochiral sequences are most dominantly represented. Possible routes for a spontaneous "mirror-symmetry breaking" process of the racemic mixtures of homochiral peptides are presented.     

On the theory of slowing down gracefully

We discuss the transport of a tracer particle through the Bose?CEinstein condensate of a Bose gas. The particle interacts with the atoms in the Bose gas through two-body interactions. In the limiting regime where the particle is very heavy and the Bose gas is very dense, but very weakly interacting (??mean-field limit??), the dynamics of this system corresponds to classical Hamiltonian dynamics. We show that, in this limit, the particle is decelerated by emission of gapless modes into the condensate (Cerenkov radiation). For an ideal gas, the particle eventually comes to rest. In an interacting Bose gas, the particle is decelerated until its speed equals the propagation speed of the Goldstone modes of the condensate. This is a model of ??Hamiltonian friction??. It is also of interest in connection with the phenomenon of ??decoherence?? in quantum mechanics. This note is based on work we have carried out in collaboration with D Egli, I M Sigal and A Soffer.