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A new enzymatic process is described. Different preparations of lipase B from Candida antarctica are able to catalyse Michaeltype addition of secondary amines to acrylonitrile. This new reaction widens the applicability of these biocatalysts in organic synthesis.

Two different macrocyclic hosts are amplified and expressed by metal guests from the same dynamic combinatorial library (DCL) of oligoimines. We studied the thermodynamic template effect and the structure of the final compounds by a combination of ESI-MS, UV and NMR spectroscopy, and Xray crystallography techniques. The use of Ba II or Cd II metal salts allows the selective synthesis of dimeric [2+2] or trimeric [3+3] cyclic structures, respectively. We observed a cooperative molding effect for the Cd ion-templated process. A study of the DCL behavior in situ demonstrated a second level of molecular diversity, based on the imine/α-methoxy-

Four diastereomeric series of N-alkylated [6+5] bicyclic isoureas having hydroxyl substituents mimicking glucose hydroxyl groups have been synthesized as potential β-glucocerebrosidase (GCase) inhibitors with the aim of developing pharmacological chaperones for enzyme deficiency in Gaucher disease (GD). The bicyclic compounds differ either by the configuration of the ring fusion carbon atoms or by the nature of the N-alkyl substituents. When assayed for effects on GCase activity, the isoureas displayed selective inhibition of GCase with low micromolar to nanomolar IC(50)'s in isolated enzyme experiments. One of the series of isoureas, a family having a specific cis ring fusion, exhibited strong inhibition of recombinant GCase activity with K(i) values in the 2-42 nM range. In addition, the [6+5] bicyclic guanidine derivatives with a substitution pattern analogous to the most active isoureas were also found to be potent inhibitors of GCase with K(i) values between 3 and 10 nM. Interestingly, the active bicyclic isoureas and guanidines also behaved as GCase inhibitors in wild-type human fibroblasts at nanomolar concentrations. The potential of these compounds as pharmaceutical chaperones was determined by analyzing their capacity for increasing GCase activity in GD lymphoblasts derived from N370S and L444P variants, two of the most prevalent Gaucher mutations. Six compounds were selected from the different bicyclic isoureas and guanidines obtained that increased GCase activity by 40-110% in N370S and 10-50% in L444P cells at low micromolar to nanomolar concentrations following a 3 day incubation. These results describe a promising series of potent GCase ligands having the cellular properties required for pharmacological chaperones.

The conformational behavior of 16- to 18-membered ring peptidomimetic p-cyclophanes 1a,b-3a,b has been studied by NMR. The cycles bearing 16 and 17 atoms showed a dynamic process within the NMR time scale, produced by the rotation of the aromatic p-diphenylene moiety with respect to the macrocyclic main plane. The temperature dependence of 1H NMR spectra has been studied in order to get activation parameters of the energetic barrier for the process (VT-NMR and line shape analysis). The rate of the movement clearly depends on the macrocyclic ring size and the nature of the peptidomimetic side chain. Entropic and enthalpic contributions to the free energy of activation are discussed. The rotation of the aromatic ring is closely related to the intramolecular hydrogen bonding pattern, as suggested by temperature factors of NH chemical shifts (DeltadeltaNH/DeltaT) and molecular modeling. The interconnected roles of the solvation and the intramolecular H-bonds have been established by measurements (VT-NMR and DeltadeltaNH/DeltaT) in environments of different polarities and H-bonding abilities. We concluded that the conformational stability of the systems directly depends on the stability of the intramolecular H-bonding pattern. We finally showed how one of these peptidomimetics behaves as a methanol-dependent artificial molecular rotor. In this simple molecular device, the well-defined molecular rotation is tuned by the competition between intramolecular hydrogen bonds and interactions with the solvent.

The reaction of the gold polymers containing bipyridyl and terpyridyl units, [Au(C≡CCHN)] and [Au(C≡CCHN)], with the water-soluble phosphines 1,3,5-triaza-7-phosphatricyclo[3.3.1.13.7]decane and 3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane gives rise to the formation of four gold(I) alkynyl complexes that self-assemble in water (HO) and dimethyl sulfoxide (DMSO), through different intermolecular interactions, with an impact on the observed luminescence displayed by the supramolecular assemblies. A detailed analysis carried out by NMR studies performed in different DMSO/deuterated HO mixtures indicates the presence of two different assembly modes in the aggregates: (i) chain assemblies, which are based mainly on aurophilic interactions, and (ii) stacked assemblies, which are based on Au···π and π···π interactions. These different supramolecular environments can also be detected by their intrinsic optical properties (differences in absorption and emission spectra) and are predicted by the changes in the relative binding energy from density functional theory calculations carried out in DMSO and HO. Small-angle X-ray scattering (SAXS) experiments performed in the same mixture of solvents are in agreement with the formation of aggregates in all cases. The aromatic units chosen, bipyridine and terpyridine, allow the use of external stimuli to reversibly change the aggregation state of the supramolecular assemblies. Interaction with the Zn cation is observed to disassemble the aggregates, while encapsulating agents competing for Zn complexation revert the process to the aggregation stage, as verified by SAXS and NMR. The adaptive nature of the supramolecular assemblies to the metal-ion content is accompanied by significant changes in the absorption and emission spectra, signaling the aggregation state and also the content on Zn.

The control of ion transport and homeostasis is a critical function of living organisms. In this perspective, an overview of different synthetic systems capable of facilitating the transmembrane transport of ions along with the biological activity exerted by these compounds is presented. Examples of both cation selective and anion selective transporters are highlighted. The potential future applications of these systems in the treatment of conditions derived from the dysregulation of natural ion transport mechanisms and the development of new antimicrobials and anticancer drugs are discussed.

The addition of DMSO to the aqueous solution of pseudopeptidic dithiols allows faster generation of dynamic combinatorial libraries of the corresponding disulphides over a wide pH range. Scheme 1 Thiol oxidation (a) and disulphide exchange (b) processes.