Michiharu Sugiura

Inhibition of advanced protein glycation by a Schiff base between aminoguanidine and pyridoxal.

Aminoguanidine is a well-known inhibitor of the formation of advanced glycation end products and is considered to be promising for the treatment of diabetic complications. We recently reported, however, that administration of aminoguanidine caused the formation of a Schiff base adduct between aminoguanidine and pyridoxal phosphate in the liver and kidney of mice and a concomitant decrease in the amount of liver pyridoxal phosphate. Our study led us to hypothesize that the Schiff base adduct and/or another Schiff base adduct formed from aminoguanidine and pyridoxal might be a better compound than aminoguanidine. In the present study, we examined the in vitro inhibitory potency of the latter adduct against advanced glycation end product formation and its effect on the tissue contents of pyridoxal and its phosphate. Aminoguanidine-pyridoxal phosphate adduct was not employed in this study because of its poor solubility in water. Aminoguanidine-pyridoxal adduct was hydrolyzed by only about 15% during 10 days at pH 7.4 and 37 degrees C. The adduct at 1 mM did not inhibit Amadori product formation induced by incubation of albumin with 100 mM mannose for 10 days. The adduct, when tested at 1 and 2 mM, dose-dependently inhibited advanced glycation end product formation induced by incubation of albumin with mannose; and the inhibitory potency of the adduct was similar to or higher than that of aminoguanidine. The presence of an appreciable amount of aminoguanidine-pyridoxal adduct in the kidney of mice given the adduct suggested that at least part of the adduct administered was absorbed from the gastrointestinal duct. The amounts of pyridoxal and its phosphate in tissues were not at all decreased by administration of the aminoguanidine-pyridoxal Schiff base. We conclude that the Schiff base may be a more promising inhibitor of advanced protein glycation than aminoguanidine.

Shock-induced carbonization of phenanthrene at pressures of 7.9-32 GPa

Abstract The chemical behavior of phenanthrene during a reaction triggered by shock waves, and its influence on the physical property of phenanthrene were studied over the pressure range of 7.9–32.0 GPa. Chemical analyses showed that shocked phenanthrene included insoluble carbonaceous material containing amorphous carbon, polycyclic aromatic hydrocarbons (PAHs) with molecular weights ranging from 128 to 356, and unreacted phenanthrene. No diamond and fullerenes were detected in the shocked phenanthrene. The results indicate that reactions triggered by shock wave are dehydrogenation, which causes carbonization and radical addition reactions, and ring cross-linking. Carbonization is the most dominant and rapidly proceeded above 20.0 GPa. Thus, an abrupt increase of compressibility of phenanthrene above 20.1 GPa previously reported is caused by the drastic carbonization.

4-Hydroxy-2-Nonenal Hardly Affects Glycolysis

4-Hydroxy-2-nonenal (HNE), one of the major products of lipid peroxidation, inactivated the rate-limiting enzymes (from animal sources) of the glycolytic pathway and the pentose phosphate pathway when incubated at 37 degrees C for 1 h in the absence of glutathione (GSH). The HNE concentration for half-maximal inactivation of 6-phosphofructokinase (PFK) and glyceraldehyde-3-phosphate dehydrogenase was 3-10 microM; and that value for pyruvate kinase, glucose-6-phosphate dehydrogenase, and hexokinases I and II was 0.15-0.6 mM. In the presence of 5 mM GSH, however, only PFK, irrespective of the source (muscle, liver, or erythrocyte), was inactivated by 40-50% when incubated with 0.1 mM HNE for 1 h. Even PFK was not inactivated in the presence of both GSH and its substrate, ATP (2 mM). Glycolysis in human erythrocytes was not affected by treatment of cells with 0.1 mM HNE at 37 degrees C for 30 min. The results suggest that HNE, at concentrations observable under physiological and pathological conditions, hardly affects glycolysis in cells.

A glycation inhibitor, aminoguanidine and pyridoxal adduct, suppresses the development of diabetic nephropathy

Abstract We examined the effect of a Schiff base adduct (PL–AG) between aminoguanidine (AG) and pyridoxal on the severity of nephropathy in streptozotocin (STZ)-induced diabetic mice using an anti-advanced glycation end product antibody. We also assessed the in vitro antioxidant activity of AG and PL–AG. Neither drug altered glycemic control. AG significantly lessened the increase in glomerular volume, fractional mesangial volume, and glomerular basement thickness, but did not alter the urinary albumin excretion (UAE). On the other hand, PL–AG significantly improved UAE. The antioxidant activity of PL–AG was superior to that of AG in all evaluation methods we employed. The findings suggest that PL–AG is superior to AG for the treatment of diabetic complications because it not only prevents vitamin B 6 deficiency, but also is better at controlling diabetic nephropathy. The preventive effect of this adduct against diabetic nephropathy would be mediated via inhibition of both oxidative stress and glycation.

Fluorous Thiazolium Salts for the Intramolecular Stetter Reaction

The fluorous thiazolium salt 6 derived from 5-(2-hydroxyethyl)-4-methylthiazole was employed for an intramolecular Stetter reaction. The catalytic activity of the fluorous catalyst 6 was similar to that of the standard catalyst 1. The fluorous catalyst 6 survived multiple reaction cycles.

Formation of 1,1-dialkoxy-1,2-dihydrocyclobuta[b]quinoline from a 1′,2′-dihydrospiro[cyclopropane-1,2′-quinoline] derivative

Abstract 1,1-Dialkoxy-l,2-dihydrocyclobuta[b]quinolines were obtained in good yields starting from 2-methylquinoline, the key intermediate being 2,2-dichloro- 1′-formyl-1′,2′-dihydrospiro[cyclopropane-1,2′-quinoline] .

Novel ring transformation of 5-(2,3,5-tri-O-benzoyl-β-d-ribofuranosyl)isoxazole-4-carbaldehyde with 1,2-diaminobenzenes to 3-cyano-1,5-benzodiazepine C-nucleosides

Syntheses of 3-cyano-7- and 8-substituted-4-(beta-D-ribofuranosyl)-1H-1,5-benzodiazepines were reported. Treatment of isoxazole carbaldehyde with 1,2-diamino-4-nitrobenzene in chloroform gave a Schiffs base, 4-(2-amino-5-nitrophenyl)iminomethyl-5-(2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl)isoxazole in 82% yield with no trace of the other regioisomer. The cyclocondensation of the resulting Schiffs base in benzene containing trifluoroacetic acid (TFA) gave 3-cyano-8-nitro-4-(2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl)-1H-1,5-benzodiazepine in 49% yield. The same reaction of isoxazole carbaldeyde with 1,2-diamino-4-methoxy- and 4-chlorobenzenes afforded the corresponding Schiffs bases. Extending the reaction time for Schiffs base gave the corresponding cyanobenzodiazepines in good yields. Debenzoylation of the compounds with sodium methoxide produced deprotected C-nucleosides.

Novel ring transformation of quinolines to indole derivatives in two steps

Abstract Dimethyl 1-methoxycarbonyl-1,2-dihydroquinoline-2-phosphonates 1a – f obtained from corresponding quinoline derivatives 2 in one step were ozonized in CHCl 3 and CH 3 COOH. Treatment of the resulting mixture with NaHCO 3 produced the 2-formyl-1-methoxycarbonylindole derivatives 5a – g in high yields. The ring transformation of quinolines 2 to indoles 5 proceeded under mild conditions.

Novel ring transformation of quinolines to indole derivatives in two steps via 1,4-dihydroquinoline derivatives

Abstract Diphenyl 1-phenoxycarbonyl-1,4-dihydroquinoline-4-phosphonates 5c – g , obtained from the reaction of corresponding quinoline derivatives 1 with phenyl chloroformate and triphenyl phosphite in one step, were ozonized in CHCl 3 and CH 3 COOH. Treatment of the resulting mixture with NaHCO 3 produced the 3-formyl-1-phenoxycarbonylindole derivatives 8a – e in high yields. The ring transformation of quinolines 1 to indoles 8 proceeds under mild conditions.

Synthesis of 4-alkoxyquinolines from quinoline Reissert compounds

The quinoline Reissert compound (5a) was converted to 1-benzoyl-3-bromo-2-cayano-1,2,3,4-tetrahydro-4-methoxyquinoline (6a) by successive treatment in methanol with bromine and q. sodium carbonate. Hydrolysis of 6a with hydrochrolic acid gave 3-bromoquinoline (4; R=H), but that with aq. sodium hydroxide afforded 4-methoxyquinoline (7a). Reissert compounds derived from some quinoline derivatives (5) gave the correspoinding 4-methoxyquinolines (7) through tetrahydroquinolines (6) in a similar way