The stereochemical alteration caused by N-methylation of an aromatic amide structure is an efficient means of changing the biological activity of a molecule, as we have found during the drug design of synthetic retinoids' and synthetic cytokinins.1 2 N-Methylbenzanilide (1) exists predominantly in a cis amide conformation in solution and in the crystal, while benzanilide (2) exists in a trans conformation.3 Though the cis conformation is superficially less favorable, this seems a rather common phenomenon intrinsic to aromatic /V-methylamides. The cause of this real stabilization of the cis structure is unclear and is under study. The cis preference can be used for the fixation of a molecule in a shape that seems less favorable from simple stereochemical considerations. In this paper, we present some examples of molecular construction by using an /V-methylamide structure as a splint or a scantling in a molecule.

The intrinsic viscosity ([eta]) and the molecular weight (M) by sedimentation equilibrium were determined for hyaluronic acids of low (M=104--7.2X10(4)) and high (M=3.1X10(5)--1.5X10(6)) molecular weights. Double logarithmic plot of [eta] against M gave different lines for the two groups. The relationship between [eta] and M was [eta]=3.0X10(6)XM1,20 for the former and [eta]=5.7X10(-4)XM0.46 for the latter group. The molecular weight at the point of intersection of the two lines was about 1.5X10(5). The rheological behavior of the hyaluronic acids below M=2.1X10(4), for which the value of reduced viscosity was independent of concentration, was different from that of the hyaluronic acids above M=5.1X10(4), for which the value of reduced viscosity increased with concentration.

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Saturated and unsaturated hyaluronate oligosaccharides were prepared from human umbilical cord hyaluronic acid by partial digestion with bovine testicular and Streptomyces hyaluronidase, respectively. After treatment with Streptomyces hyaluronidase, the distribution of degradation products from these oligosaccharides was determined. Octasaccharides, either saturated or unsaturated, were substrates of the minimum size. Tetra- and hexasaccharides were not degraded further and remained as final products. This indicates that at least four succeeding N-acetylhyalobiuronosyl residues were required for this enzymatic degradation. Since unsaturated oligosaccharides were more susceptible to this enzyme than saturated ones of the same polymerization degree, and inner glucosaminidic linkages were cleaved in preference to those at the outermost sites, some groups adjacent to this segment seemed to influence the susceptibility of the oligosaccharide to this enzyme.

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In order to clarify the subsite structure of ribonuclease A (RNase A), the interactions of pdTp, pAp, dTpdAp, and pdTpdAp with RNase A were investigated by means of kinetic studies and 31P NMR spectroscopy. The pH profile of the 31P NMR spectrum of RNase A-pdTp complex indicated the interaction of the 3'- and 5'-phosphates with RNase A. The signal of 3'-phosphate of pdTp in the presence of RNase A gave a characteristic titration curve indicating the participation of more than 2 ionic groups in the P1 subsite. A similar 31P NMR titration was observed in the case of 5'-phosphate of pAp in the presence of RNase A. The results indicated that pAp interacted with RNase A at the P1, B2, and P2 sites. dTpdAp and pdTpdAp inhibited RNase A action more markedly than dTpdA, indicating the contribution of 3'- and 5'-terminal phosphate groups attached to dTpdA to the affinity of RNase A. The 31P NMR spectra of RNase A-dTpdAp and pdTpdAp complexes excluded the possible interaction of the monoester type phosphate of the inhibitors with the P1 site of RNase A, thus indicating the binding of the 3'-side phosphates with the P2 subsite of RNase A.

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