We have previously shown that macrotricyclic host 1a is a powerful receptor for glucopyranosyl units in the nonpolar medium of chloroform. However, the solubility properties of 1a did not permit studies of the extraction of carbohydrates from aqueous solution. This paper describes the synthesis of the new variant 1b, furnished with a highly lipophilic exterior array of 12 benzyloxy substituents. In homogeneous solution, 1b behaves much as 1a, binding n-octyl ␤-D-glucoside with Ka ‫؍‬ 720 M ؊1 in CD3OH͞CDCl3 (8:92). In twophase experiments, the improved solubility of 1b allows carbohydrate extraction to be observed. Three hexoses (glucose, galactose, and mannose), two pentoses (ribose and xylose), and the two methyl glucosides are all extracted substantially into chloroform from 1 M aqueous solutions. Among the hexoses, 1b shows notable affinity and selectivity for glucose, extracting detectable amounts even from 0.1 M aqueous solutions. C arbohydrate recognition is an active area of supramolecular chemistry, motivated by the biological importance of saccharides and also by the unusual challenge represented by these complex substrates (1-13). On the one hand, carbohydrates must be recognized and processed during metabolism, whereas saccharide motifs are known to mediate cell-cell recognition, the infection of cells by pathogens, and many aspects of the immune response (14-17). On the other, carbohydrates possess structures that are fairly large, irregular, and multivalent, while being quite similar to clusters of water molecules. Even in nonpolar solvents, selective carbohydrate receptors require extended, sophisticated architectures (1, 3-6). In the presence of liquid water, the problem becomes yet more difficult. Recognition by means of boronate formation has been relatively successful (2, 7-10), but there are few effective systems for binding saccharides from water by using noncovalent bonds (1, 11-13).A receptor can be shown to discriminate between saccharide and water in one of two ways. Firstly (and most obviously), it can be studied in homogeneous aqueous solution. Secondly, it can be designed for solubility in nonpolar media and studied in a two-phase system, demonstrating the ability to extract or transport the carbohydrate (18)(19)(20)(21)(22)(23)(24). This latter approach is directly relevant to the transport of carbohydrates across biological membranes. Boron-based systems have again proved quite effective (22-24). However, for those receptors operating through noncovalent interactions, success has been limited thus far. Positive results have been obtained with the less hydrophilic saccharides at high aqueous concentrations (18, 20), but not in general with the more hydrophilic substrates such as glucose. § Recently we described the tricyclic tetraester 1a (Fig. 1), a novel receptor that showed an exceptional affinity for n-octyl ␤-D-glucoside, remarkable ␤ vs. ␣ selectivity, and the unusual ability to dissolve solid glucose in CHCl 3 (25). Although we hoped to demonstrate the extraction of glucose ...

This paper describes the design and implementation of elements of an integrated competency-focused pharmacy programme in the School of Pharmacy and Pharmaceutical Sciences (SoPPS), Trinity College Dublin (TCD), Ireland. Following a national review of pharmacy education and training in Ireland in 2010, and subsequent publication of legislation in 2014, the School has implemented a five-year integrated programme of pharmacy education and training, leading to the award of a Master’s degree in Pharmacy (M. Pharm.). Curricular integration has been achieved by underpinning the new programme with a national competency framework for pharmacists and through the utilisation of curricular integration themes. Programme integration also encompasses embedded experiential learning placements in Years 2, 4 and 5 of the five-year programme. The new five-year integrated pharmacy programme, which commenced in 2015, replaced the 4 + 1 model of education and training where a four-year Bachelor’s degree was followed by a one-year internship, which was a distinct and separate element of the students’ training.

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Dipicolinoyl spacer groups are used to control the conformational and H-bonding properties of tricyclic carbohydrate receptors 3 and 4. Binding selectivities are changed in relation to all-isophthaloyl system 1b.

Kinetic studies of the acidic hydrolysis of diazepam and nitrazepam were carried out in the presence of micelles of sodium dodecyl sulfate (sds). The hydrolysis of diazepam was shown to occur with biphasic kinetics. This is consistent with initial hydrolysis of the azomethine bond followed by very slow hydrolysis of the amide bond as found for hydrolysis in aqueous solution. Nitrazepam, however, was found to decompose with monophasic kinetics consistent with initial amide hydrolysis. Reactions involving the hydrolysis of the azomethine bond were shown to be independent of acid concentration and subject to inhibition by micelles of sds. Reactions involving amide hydrolysis were shown to be first order in acid concentration and subject to micellar catalysis. The mechanistic change for the hydrolysis of nitrazepam on transfer from water (initial azomethine cleavage) to micelles of sds (initial amide cleavage), was presumably the result of the inhibition of azomethine hydrolysis and the catalysis of amide hydrolysis by the micelles.

A,A'-Diisopropyldiaminomaleonitrile (4) is oxidized by oxygen to , '-diisopropyldüminosuccmonitrile (5) in 47% yield in acetonitrile solution. The yield of 5 is much less in aqueous solution at pH 9.2 with monoisopropylurea as the other reaction product. Ammoniacal hydrolysis of 5 (0.1 mmol) gives urea (0.076 mmol) as the only reaction product, while hydrolysis in the presence of a 30-fold excess of cyanide gives an enhanced yield of urea (0.28 mmol). These results may be explained by the reduction of 5 to 4 by cyanide with the subsequent formation of cyanogen or cyanate which in turn reacts with ammonia to give urea. Oxygen oxidizes 4 to 5, thus completing the cycle. Diaminomaleonitrile (3) is air oxidized in aqueous ammonia (pH 9.2) and urea was detected as a reaction product. Diiminosuccinonitrile ( 6) is the most likely initial oxidation product of 3. A 50% yield of urea is obtained on hydrolysis of 6 in ammonical solution. However, this yield did not increase when the hydrolysis was performed in the presence of cyanide. A pH 9.2 solution of cyanide in the presence of oxygen decomposes more rapidly than one which has been degassed. The detection of urea and amino acids (after acid hydrolysis) from the degassed cyanide solution demonstrates that oxidation and reduction leading to urea and the amino acid precursors are taking place in the absence of oxygen, suggesting that these reactions were feasible on the primitive earth.

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The lysyl ester analogue p-nitrophenyl alpha-amino-p-toluate hydrobromide was synthesized, and its reactions with thrombin, trypsin, and plasmin were studied by stopped-flow and conventional methods. Kinetic parameters were compared with those determined for the arginyl ester analogue, p-nitrophenyl p-guanidinobenzoate hydrochloride, with these enzymes. By following nitrophenol release or proflavin absorption changes in the stopped-flow spectrophotometer, the constants Ks (enzyme-substrate binding), k2 (acylation), and k3 (deacylation) were determined. The major findings were: (1) Ks values were similar regardless of the substrate or the enzyme; (2) k3 was approximately the same for the reaction of the lysyl ester analogue with any enzyme; (3) k2 for the lysyl ester analogue was 1100 times greater with trypsin than with thrombin; and (4) k2 with thrombin was 60 times greater for the arginyl than for the lysyl ester analogue. The results suggest that the limited cleavage of lysyl bonds by thrombin is due in part to restricted acylation rather than substrate binding. The active site of thrombin, compared with that of trypsin, appears to have a more stringent requirement for the spatial relationship between the cationic group and the bond cleaved in substrates.