Liliane Lacombe

Channel-type molecular structures. Part 4. Transmembrane transport of alkali-metal ions by ‘bouquet’ molecules

This report describes transport experiments with ‘bouquet’ molecules designed to act as artificial ion channels. The ‘bouquets’ are based on a central macrocycle which is either an 18-crown-6 (BM) or a cyclodextrin derivative (BCD) to which are attached polyethylene oxide [poly(oxyethylene)] chains (BMo and BCDo) or polyalkyl chains (BMc and BCDc) tipped with carboxylate endgroups. The ‘bouquets’ were studied in liposomes prepared from egg phosphatidylcholine (egg PC), dipalmitoyl phosphatidylcholine (DPPC) and a mixture of egg PC, stearylamine and cholesterol. Opposing gradients in Li+ and Na+ concentration were created and the transport of alkali-metal ions down their concentration gradients was followed directly by 7Li and 23Na NMR spectroscopy. ‘Bouquets’ were found to cause a one-for-one exchange of Na+ for Li+(antiport). In order to estimate transport rates, the extent of Na+ entry into liposomes was followed as a function of time. All ‘bouquets’ transported ions at similar rates in fluid membranes. Comparison of transport rates in fluid-(egg PC) and gel-state membranes (DPPC) was used to distinguish carrier and channel mechanisms. Control experiments demonstrated that a known carrier (monensin A) gave significantly lower transport rates in gel-state membranes. Two ‘bouquets’, BMc and BCDc, were found to transport Na+ at similar rates in fluid- and gel-state membranes; this suggests that ion passage occurs preferentially by the channel mechanism and not by the carrier mechanism. Variation of transport rate with ‘bouquet’ concentration was probed for BMo and BMc and the rates were found to increase with BMc concentration but not with BMo concentration. Since the transport rate is expected to be proportional to transporter concentration in both the carrier and channel mechanisms, this indicates that BMo uses neither a carrier nor a channel mechanism. The mechanism by which ‘bouquet’ molecules operate and the criteria which may be used to decide whether functioning channels have been created are discussed.

Analysis of the conformational behaviour of perfunctionalized β-cyclodextrins. Part 1. Evidence for insertion of one of the rim substituents into the cyclodextrin cavity in organic solvents

Several functionalized β-cyclodextrins have been shown to exhibit conformational isomerism. The analysis of the conformational behaviour of several derivatives strongly suggests that a slow exchange occurs between C7 and C1 conformers, the C1 probably involving insertion of one of the primary rim substituents in the cyclodextrin cavity. The significance of the structural features of cyclodextrin substituents for the occurrence of conformational isomerism is examined. The relevance of the use of cyclodextrins for the design of molecular devices is discussed.

Synthesis of 2-dimethylaminoimidazole derivatives: a new access to indolyl-imidazole alkaloids of marine origin.

Abstract The first preparation of 2-dimethylaminoimidazole 1a , a structural feature of several marine products was undertaken and its reactivity investigated. The synthesis of natural alkaloids 5 and 12b was achieved by direct coupling of the easily accessible oxidized 2-dimethylaminoimidazoles 7 and 8 with indole-3-carboxaldehyde and indole respectively, demonstrating the usefulness of this approach for other structurally related natural products.

An approach to channel-type molecular structures. Part 3. Incorporation studies of the bouquet-shaped BM and BCD in phosphatidylcholine vesicles

Incorporation of bouquet-shaped molecules based either on a macrocyclic (BM) or on a β-cyclodextrin (BCD) core in phosphatidylcholine vesicular bilayers has been investigated. As can be shown by numerous techniques, these molecules are incorporated in moderate to high yields within vesicle membranes. Possible incorporation modes are then discussed.

Binding of acetylcholine and other molecular cations by a macrocyclic receptor molecule of speleand type

The chiral tetracarboxylic macrocycle (1) is a receptor molecule of the speleand type which binds strongly quaternary as well as primary ammonium cations, in particular acetylcholine and methylviologen.

Synthesis of biologically active fluorescent phorbol esters

Abstract Pure fluorescent derivatives of 12-O-tetradecanoyl phorbol-13-O-acetate (TPA), labeled in the tetradecanoyl chain, are synthesized by two ways: 1) from both enantiomers of β-N-dansylaminotetradecanoic acid which requires the resolution of the (±) β-aminoacid precursor; 2) from an achiral fluorescent chain derived from 3-azatetradecanoic acid. The new phorbol derivatives retain the main biological activity of TPA.

Synthesis of microsequential methylvinylsiloxane–dimethylsiloxane copolymers by nonequilibrium copolymerization

Nonequilibrium anionic ring-opening copolymerization of 1,3,5,7-tetramethyl-1,3,5,7-tetravinylcyclotetrasiloxane (V4) with hexamethylcyclotrisiloxane (D3) was examined as a route to methylvinyl–dimethylsiloxane microsequential copolymers. The copolymerization was carried out in toluene and was initiated with Me3SiCH2Li using DMSO as the promoter. Distribution of siloxane units obtained from kinetic analysis based on first-order Markovian statistics was compared with that found from analysis by 29Si NMR spectroscopy. Results showed that although chain transfer and back-biting play some role in this system, the kinetics of copolymerization may be described to a reasonable approximation by the first-order Markov model.

Water-soluble cryptophane binding lipophilic guests in aqueous solution

The first water-soluble cryptophane (4) has been synthesized in three steps from cryptophane-A (1); (4) has been found to complex chloroform and dichloromethane strongly in D2O, with binding constants in the range 103–104 dm3/mol.

Resolution of γ-methyl and γ-fluoroglutamic acids. Lack of stereospecificity of leucine aminopeptidase with L-leucyl-L-erthro-γ-substituted glutamates

The hydrolysis of L-leucyl-γ-substituted D,L-glutamates by leucine aminopeptidase, from porcine kidney, is stereospecific with erythro-γ-methyl and erytho-γ-fluoroglutamate containing dipeptides whereas there is a lack of stereospecificity with the erytho-isomers. The optical purities of L-threo- and L-erythro-glutamate isomers thus obtained have been monitored by gas chromatography, high pressure liquid chromatography, or nuclear magnetic resonance. The optical rotations of optically pure L-isomers have been measured and the discrepancies with former publications are discussed.