In our studies of Na(+)-glucose cotransporter (SGLT) inhibitors as antidiabetic agents, a series of novel 4'-dehydroxyphlorizin derivatives substituted on the B ring was prepared and their effects on urinary glucose excretion were evaluated in rats. Introduction of only a small alkyl group at the 4'-position increased the activity, and 3-(benzo¿bfuran-5-yl)-2',6'-dihydroxy-4'-methylpropiophenone 2'-O-beta-D-glucopyranoside (4) showed the most potent effect. To overcome hydrolysis of compound 4 by beta-glucosidase in the digestive tract, the OH groups on the glucose moiety of compound 4 were modified. Three prodrugs (5, 42, and 55) were more potent than the parent compound 4 by oral administration, and finally 3-(benzo¿bfuran-5-yl)-2',6'-dihydroxy-4'-methylpropiophenone 2'-O-(6-O-methoxycarbonyl-beta-D-glucopyranoside) (5) was selected as a new promising candidate. Compound 5 was metabolized mainly by liver esterase to the active form (4), which was about 10 times more potent than 5 in inhibiting SGLT. In oral glucose tolerance test in db/db mice, compound 5 dose-dependently suppressed the elevation of glucose levels. Single administration of 5 reduced hyperglycemia concurrently with increase of glucose excretion into urine in diabetic KK-A(y) mice. Furthermore, compound 5 suppressed the elevation of blood glucose levels but did not lower it below the normal level even in fasted conditions in KK-A(y) mice. Additionally, long-term treatment with 5 dose-dependently reduced hyperglycemia and HbA1c in KK-A(y) mice. These pharmacological data strongly suggest that compound 5 has a therapeutic potential in the treatment of NIDDM.
The molecular characteristics and the chain stiffness were investigated for fractionated samples of cellulose diacetate (CDA, degree of substitution DS = 2.40) in N, N-dimethylacetamide (DMAc) through the partial specific volume, the viscometric, the sedimentation velocity, and the sedimentation equilibrium measurements at 30 °C. It was found that CDA dispersed molecularly in DMAc under the external field such as in the viscometric and the sedimentation experiments. The molecular weight dependence of the intrinsic viscosity [η] and the sedimentation coefficient at infinite dilution s0 of the single CDA molecule were expressed by the relation [η] = 1.10×10−2Mw0.85 (cm3 g−1) and s0=2.25×10−14Mw0.20 (s), which exhibit the stiff, or semiflexible chain nature. The semiflexible chain parameters were evaluated by the Yamakawa–Fujii (YF) theory of the unperturbed wormlike cylinder model, first via a combination of the viscosity and the partial specific volume data (method A) and second via a combination of the sedimentation and the partial specific volume data (method B). Method A gave the chain parameters that q = 8.0 nm, ML = 523 nm−1, and d = 0.89 nm, whereas method B gave q = 48 nm, ML = 560 nm−1, and d = 0.93 nm. Here q is the persistence length, ML is the molecular weight per unit contour length, and d is the chain diameter of the wormlike cylinder model. Methods A and B deduce, independent of the method, the definite ML and d values, which are very consistent with the ordinary reported values. However, q estimated by the two methods differs by about six times the other. This fact suggests that the CDA molecule in the ultracentrifugal field has a conformation different from that in the viscometric shear field: The CDA chain may be highly stiff in the ultracentrifuge because of the situation that the adjacent glucose residues are stuck in a rigid conformation by the double stapled hydrogen bonds between the intramolecular hydroxyls and oxygens.
In the quiescent state, dynamic light scattering measurements were performed for a polysaccharide, cellulose diacetate (CDA, the degree of substitution 2.40), in a liquid-crystalline promoting solvent N, N-dimethylacetamide (DMAc) in the range from dilute to crossover concentrations. Three modes of motions were detected simultaneously over all concentrations measured. They are in a nest of structures, which are caused by long-range interactions acting between OH groups of glucose units in a highly dielectric-constant solvent DMAc. Denoting these modes as Mode I, II, and III from fast to slow motions, the decay rates Γ of each mode showed the squared scattering-vector dependence at lower angles, i.e., the diffusion nature. In dilute solution, fast Mode I is the translational diffusion of a single CDA chain and others represent the dissipation of locally associated CDA clouds which grow by the interactions specified above. Mode II is related to a coarse cloud formed in a limited time but spread over a wide space A, while Mode III is related to a dense cloud created with a very small space B inside >A. The tentative increase in CDA concentrations in the spaces A and B relaxes to the level of bulk concentration with a large decay rate ΓII for Mode II and a small ΓIII for Mode III. With the increase of c, the number of A and the bulk concentration increase, and the decay rate ΓIII for dissipating B becomes smaller than that in dilute solution. Above the crossover concentration c*, however, the space A becomes close each other and almost all the CDA are packed in A. Then fast Mode I represents the relaxation of concentration fluctuations, or cooperative diffusion, with the length scale as small as a single CDA chain, ξI. Mode II represents another cooperative diffusion, which is originated by the relaxation of concentration fluctuations effective only in A of the correlation length ξII. Mode III is related to the time–space fluctuation in the distribution of A, which emerges as another cooperative diffusion of much larger correlation length ξIII. Mode II was contaminated by a self-diffusionlike (SF) motion, though both were separated into two branches in more concentrated regions. The SF mode is assigned to a reptation motion of CDA, which can be described by the constrained translational motion of a stiff chain in the tube with interacting wall. The dynamical feature of these modes of motions are influenced strongly by strength and nature of long-range interactions between unsubstituted OH groups in glucose residues, or the hydrogen bonds in solvents of high electronegativity.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.