Many polysaccharide chains can adopt ordered helical and ribbon-like secondary structures. It seems however that these chains are often so stiff and extended that the cooperative interactions necessary for stability in the solvent environment can only be achieved when inter-chain as well as intra-chain interactions are favorable. Hence we commonly find two-or more-stranded associations of helices, of ribbons, or of helices with ribbons. These can be regarded as tertiary and higher levels of structure. The ordered secondary structure characteristically requires a regular repeating sequence of sugar residues, and the termination of this sequence by insertion of a residue of different type may also terminate the secondary structure and hence the association in which it is involved. This is the mechanism by which native polysaccharides may link up to form three dimensional networks, or gels, in which state they perform their natural roles in maintaining the hydration and integrity of biological tissues. For several polysaccharides there is evidence that the mechanism of biological control over the fine topology and properties of the gel network is mediated by enzymes which modify sugar residues at the polymer level to change the pattern of "interrupting" sugar residues.
Complete assignments are given for the 'H nuclear magnetic resonance (NMR) spectra at 300 MHz of chondroitin 4-sulphate, chondroitin 6-sulphate and hyaluronate in deuterium oxide solution, supported by spin decoupling and computer simulation. Coupling constants and chemical shifts are as expected from spectra of the model glycosides, methyl fl-D-glucopyranosiduronate, methyl 2-acetamido-2-deoxy-~-~-glucopyranoside and methyl 2-acetamido-2-deoxy-~-~-galactopyranoside, when allowance is made for systematic influences on chemical shifts of interglycosidic linkages and sulphate substitution.As reported elsewhere, addition of alkali causes the hyaluronate spectrum to sharpen considerably. This is taken to indicate that segmental motion is enhanced by disruption of some system of inter-residue bonding on ionisation of hydroxy groups. Concomitant changes in chemical shifts are seen mainly for H-2 of the glucuronate residue, and the CH3 and H-2 of the acetamidodeoxyglucose residue. Similar effects are not seen for chondroitin sulphates, either in line widths or chemical shifts.Comparison of the spectra of hyaluronate, chondroitin sulphates, and the model glycosides, indicates that proton chemical shifts are sensitive to the conformation differences between the polysaccharides in alkaline solution, but do not detect the differences in neutral solution that are known from NMR relaxation to be present. The altered configuration and/or substitution pattern of the acetamidodeoxyhexose residue in hyaluronate compared with chondroitin sulphates appears to have a critical influence on overall conformation in both alkaline and neutral solution.Although the solution conformation of hyaluronate (formula I) is clearly established by hydrodynamic methods as a random coil to the first approximation [l -31, several of its properties are unexpected on this basis. The bulk viscosity increases at higher values of ionic strength (Morris, Rees and Welsh, unpublished work), which is the opposite of expectation for a classic polyelectrolyte coil and may have its origin in fleeting but specific intermolecular Abbreviations. 13C-NMR, carbon-13 nuclear magnetic resonance; GlcUA, p-11-glucopyranosiduronate; GlcNAc, 2-acetamido-2-deoxy-~-~-glucopyranoside; GalNAc, 2-acetamido-2-deoxy-B-~-galactopyranoside; H-NMR, proton nuclear magnetic resonance; ppm, parts per million (on 6 chemical shift scale); Tz, spin-spin (or transverse) relaxation time.Enzyme. Ovine testicular hyaluronidase (EC 3.2.1.35).
6
COCH3-n
Structure-based design was applied to the optimization of a series of 2-(quinazolin-2-yl)phenols to generate potent and selective ATP-competitive inhibitors of the DNA damage response signaling enzyme checkpoint kinase 2 (CHK2). Structure-activity relationships for multiple substituent positions were optimized separately and in combination leading to the 2-(quinazolin-2-yl)phenol 46 (IC(50) 3 nM) with good selectivity for CHK2 against CHK1 and a wider panel of kinases and with promising in vitro ADMET properties. Off-target activity at hERG ion channels shown by the core scaffold was successfully reduced by the addition of peripheral polar substitution. In addition to showing mechanistic inhibition of CHK2 in HT29 human colon cancer cells, a concentration dependent radioprotective effect in mouse thymocytes was demonstrated for the potent inhibitor 46 (CCT241533).
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