Bruce L. May

Natural and synthetic forms of insulin-like growth factor-1 (IGF-1) and the potent derivative, destripeptide IGF-1: biological activities and receptor binding.

Insulin-like growth factor-1 (IGF-1), whether recombinant, chemically-synthesised or purified from bovine colostrum, was equipotent in radioreceptor assays with IGF-1 or insulin-like growth factor-2 (IGF-2) as radioligand as well as in its ability to stimulate protein synthesis in L6 myoblasts. The N-terminal truncated, destripeptide derivative of IGF-1 was approximately 7 times more potent than IGF-1 in the protein synthesis bioassay. This increased activity occurred equally with the peptide purified from bovine colostrum as with chemically-synthesised material. The higher potency of the truncated form was not associated with an increased ability to compete for IGF-1 binding to L6 myoblasts.

Substituent effects and chiral discrimination in the complexation of benzoic, 4-methylbenzoic and (RS)-2-phenylpropanoic acids and their conjugate bases by β-cyclodextrin and 6A-amino-6A-deoxy-β-cyclodextrin in aqueous solution: potentiometric titration and 1H nuclear magnetic resonance spectroscopic study

A potentiometric titration study in aqueous solution (l= 0.10 mol dm–3, KCl) of the complexation of benzoic, 4-methylbenzoic and (RS)–2-phenylpropanoic acids (HA) and their conjugate bases (A–) with β-cyclodextrin, βCD, and its substituted analogue, 6A-amino-6A-deoxy-β-cyclodextrin, βCDNH2, in which a primary hydroxy group is replaced by an amino group which may be protonated to produce a singly charged species, βCDNH+3, is reported. At 298.2 K the stability constants for the complexes have the values (in dm3 mol–1) shown in parentheses: benzoic acid ·βCD (K1HA= 590 ± 60); benzoate ·βCD (K1A= 60 ± 10); benzoic acid ·βCDNH+3(K2HA= 340 ± 30); benzoate ·βCDNH+3(K2A= 120 ± 20); benzoate ·βCDNH2(K3A= 50 ± 20); 4-methylbenzoic acid ·βCD (K1HA= 1680 ± 90); 4-methylbenzoate ·βCD (K1A= 110 ± 1); 4-methylbenzoic acid ·βCDNH+3(K2HA= 910 ± 20); 4-methylbenzoate ·βCDNH+3(K2A= 330 ± 20); and 4-methylbenzoate ·βCDNH2(K3A= 100 ± 20). These data indicate that for a given cyclodextrin the guest carboxylic acids form complexes of higher stability than do their conjugate base analogues, and that βCDNH+3 forms more stable complexes with the conjugate bases than do βCD and βCDNH2. These trends are also observed for the complexation of (RS)-2-phenylpropanoic acid and (RS)-2-phenylpropanoate where the complexes indicated are characterised by the stability constants (in dm3 mol–1) shown in parentheses: (RS)-2-phenylpropanoic acid ·βCD (K1RHA= 1090 ± 30, K1SHA= 1010 ± 40); (RS)-2-phenylpropanoate ·βCD (K1RA= 63 ± 8, K1SA= 52 ± 5); (RS)-2-phenylpropanoic acid ·βCDNH+3(K2RHA= 580 ± 20, K2SHA= 480 ± 10); (RS)-2-phenylpropanoate ·βCDNH+3(K2RA= 150 ± 8, K2SA= 110 ± 10); and (RS)-2-phenylpropanoate ·βCDNH2(K3RA= 36 ± 6, K3SA= 13 ± 7). These data also show that while K1RHA and K1SHA, and K1RA and K1SA are indistinguishable for (RS)-2-phenylpropanoic acid ·βCD and (RS)-2-phenylpropanoate ·βCD, chiral discrimination is indicated by K2RHA > K2SHA for (RS)-2-phenylpropanoic acid ·βCDNH+3, K2RA > K2SA for (RS)-2-phenylpropanoate ·βCDNH+3, and K3RA > K3SA for (RS)-2-phenylpropanoate ·βCDNH2. The 1H NMR spectra of the methyl groups of the enantiomers of (RS)-2-phenylpropanoic acid appear as two separate doublets, indicating chiral discrimination when complexed by βCD or βCDNH+3, but such chiral discrimination is not observed for (RS)-2-phenylpropanoate when complexed by βCDNH+3. The implications of these observations are discussed.

Tailoring Polymeric Hydrogels through Cyclodextrin Host―Guest Complexation

A close correllation between molecular-level interactions and macroscopic characteristics of polymer networks exists. The characteristics of the polymeric hydrogels assembled from β-cyclodextrin (β-CD) and adamantyl (AD) substituted poly(acrylate)s can be tailored through selective host-guest complexation between β-CD and AD substituents and their tethers. Dominantly, steric effects and competitive intra- and intermolecular host-guest complexation are found to control poly(acrylate) isomeric inter-strand linkage in polymer network formation. This understanding of the factors involved in polymeric hydrogel formation points the way towards the construction of increasingly sophisticated biocompatible materials.

Tryptophan anion complexes of β-cyclodextrin (cyclomaltaheptaose), an aminopropylamino-β-cyclodextrin and its enantioselective nickel(II) complex

6I-(3-Aminopropylamino)-6I-deoxy-cyclomaltaheptaose (βCDpn) exhibits enhanced complexation of tryptophan anion, by comparison with βCD, while the nickel(II) complex of βCDpn complexes tryptophan anion even more strongly and exhibits a tenfold enantioselectivity in favour of the (S)-tryptophan anion.

Diazacoronand linked β-cyclodextrin dimer complexes of Brilliant Yellow tetraanion and their sodium(I) analogues

Complexation of the Brilliant Yellow tetraanion, 3(4-), by two new diazacoronand linked beta-cyclodextrin (beta CD) dimers 4,13-bis(2-(6A-deoxy-beta-cyclodextrin-6A-yl)aminooctylamidomethyl- and 4,13-bis(8-(6A-deoxy-beta-cyclodextrin-6A-yl)aminooctylamidomethyl)-4,13- diaza-1,7,10-trioxacyclopentadecane, 1 and 2, respectively, has been studied in aqueous solution. UV-visible spectrophotometric studies at 298.2 K, pH 10.0 and I = 0.10 mol dm-3 (NEt4ClO4) yielded complexation constants for the complexes 1 x 3(4-) and 2 x 3(4-), K1 = (1.08 +/- 0.01) x 10(5) and (6.21 +/- 0.08) x 10(3) dm3 mol-1, respectively. Similar studies at 298.2 K, pH 10.0 and I = 0.10 mol dm-3 (NaClO4) yielded K3 = (4.63 +/- 0.09) x 10(5) and (3.38 +/- 0.05) x 10(4) dm3 mol-1 for the complexation of 3(4-) by Na+ x 1 and Na+ x 2 to give Na+ x 1 x 3(4-) and Na+ x 2 x 3(4-), respectively. Potentiometric studies of the complexation of Na+ by 1 and 2 by the diazacoronand component of the linkers to give Na+ x 1 and Na+ x 2 yielded K2 = (2.00 +/- 0.05) x 10(3) and (1.8 +/- 0.05) x 10(3) dm3 mol-1, respectively, at 298.2 K and I = 0.10 mol dm-3(NEt4ClO4). For complexation of Na+ by 1 x 3(4-) and 2 x 3(4-) to give Na+ x 1 x 3(4-) and Na+ x 2 x 3(4-) K2K3/K1 = K4 = 8.6 x 10(2) and 9.8 x 10(3) dm3 mol-1, respectively. The pKaS of 1H4(4+) are 7.63 +/- 0.01, 6.84 +/- 0.02, 5.51 +/- 0.04 and 4.98 +/- 0.03, and those of 2H4(4+) are 8.67 +/- 0.02, 8.11 +/- 0.02, 6.06 +/- 0.02 and 5.14 +/- 0.05. The larger magnitude of K1 for 1 by comparison with K1 for 2 is attributed to the octamethylene linkers of 2 competing with 3(4-) for occupancy of the annuli of the beta CD entities while the competitive ability of the dimethylene linkers of 1 is less. A similar argument applies to the relative magnitudes of K3 for Na+ x 1 and Na+ x 2. Increased electrostatic attraction probably accounts for K3 > K1 for Na+ x 1 x 3(4-) and 1 x 3(4-) and for Na+ x 2 x 3(4-) and 2 x 3(4-). The lesser magnitudes of K2 and K4 for Na+ x 1 and Na+ x 1 x 3(4-) compared with those for Na+ x 2 and Na+ x 2 x 3(4-) are attributed to the octamethylene linkers of 2 producing a more hydrophobic environment for the diazacoronand than that produced by the dimethylene linkers of 1. 1H NMR spectroscopic studies and the syntheses of 1 and 2 are described.

Complexation of Methyl Orange and Tropaeolin 000 No. 2 by β-cyclodextrin dimers

Spectrophotometric studies of the complexation of Methyl Orange (MO - ) and Tropaeolin 000 No. 2 (TR - ) anions by dimeric N,N′-bis(6 A -deoxy-6 A -β-cyclodextrin)urea (βCD) 2 ur and its oxalamide and succinamide analogues, (βCD) 2 ox and (βCD) 2 su, respectively, are consistent with the predominant formation of complexes of the general formulae (βCD) 2 x·MO - characterized by stability constants K 1 =(1.05±0.04)×10 5 , (1.92±0.04)×10 5 and (2.50±0.02)×10 4 dm3 mol -1 and (βCD) 2 x·TR - characterized by K 1 =(1.39±0.03)×10 4 , (7.4±0.1)×10 3 and (4.60±0.05)×10 3 dm3 mol -1 , in aqueous phosphate buffer at pH 9.0 and 5.5 and 298.2 K. These values are significantly greater than K 1 =2160 and 710 dm3 mol -1 for the β-cyclodextrin complexes, βCD·MO - and βCD·TR - and are indicative of cooperative binding in (βCD) 2 x·MO - and (βCD) 2 x·TR - . The factors affecting complex stability are discussed and comparisons are made with related systems.

Preparation and characterization of 6A-polyamine-mono-substituted β-cyclodextrins

General syntheses for eleven β-cyclodextrins (cyclomaltoheptaoses) mono-substituted at the C6 position by a polyamine are described. The basis of the synthesis is the reaction of 6A-O-(4-methylphenylsulfonyl)-β-cyclodextrin in the presence of KI in 1-methylpyrrolidin-2-one solution. This produces a clean product and obviates the substantial purification procedures which other preparative methods often entail. Systematic studies of the variations of the pKas of the protonated amine groups and the 13C NMR spectra of the modified β-cyclodextrins with pH are reported.

A Versatile Synthesis of Linked Cyclodextrins

Reactions of amino-substituted cyclodextrins with bis(3-nitrophenyl) oxalate, malonate, succinate and glutarate, and with diphenyl carbonate, afford a range of linked cyclodextrins. These include α- and β-cyclodextrin dimers, joined by substitution at either C6 or C3, and asymmetric species with a β-cyclodextrin bonded to an a-cyclodextrin and a C3-substituted cyclodextrin attached to a C6-substituted moiety.

A new α-haloglycine template for the asymmetric synthesis of amino acid derivatives

Abstract Reaction of (S)-N,N-diacylvalylglycine anhydride with N-bromosuccinimide afforded the corresponding α-bromoglycine derivative, which reacted diastereoselectively with allyltributyltin and deuterium) over palladium chloride to give the corresponding α-allyl- and α-deuterio-glycine derivatives, respectively.

Chiral differentiation in the deacylation of 6A-O-{2-[4-(2-methylpropyl)phenyl]propanoyl}-β-cyclodextrin

In 0.1 mol dm–3 sodium carbonate buffer at pH 11.5 the pseudo first-order rate constants for the hydrolysis of the diastereoisomers of the title compound to give Ibuprofen {2-[4-(2-methylpropyl)phenyl]propanoic acid} and β-cyclodextrin are 2.97 × 10–5 s–1 and 3.16 × 10–4 s–1, with the diastereoisomer derived from (R)-Ibuprofen being the most susceptible to hydrolysis.