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Properties and efficacies of novel aldose reductase (AR) inhibitors, M16209 (1-(3-bromobenzo[b]furan-2-ylsulfonyl)hydantoin) and M16287 (1-(3-chlorobenzo[b]furan-2-ylsulfonyl)hydantoin), were examined in vitro and in vivo, compared with known AR inhibitors, ONO-2235 and sorbinil. These four compounds inhibited partially purified aldose reductases from various origins, and the potencies of M16209 and M16287 were on the whole similar to ONO-2235, and were greater than that of sorbinil. The IC50 values of the four AR inhibitors did not substantially depend on the substrate used. Kinetic studies of inhibition of partially purified bovine lens (BLAR) revealed that M16209, M16287 and sorbinil were uncompetitive with glyceraldehyde and noncompetitive with nicotineamide adenine dinucleotide phosphate (NADPH), whereas ONO-2235 was noncompetitive with both glyceraldehyde and NADPH. Aldose reductase became less sensitive to the four inhibitors as enzyme purification progressed, although the susceptibility to inhibition was partially reversed by incubation with dithiothreitol. In addition, the four compounds slightly affected those enzymes of carbohydrate and glutathione metabolism which were tested. M16209 and M16287 prevented sorbitol accumulation in isolated rat tissues as potently as ONO-2235 and sorbinil. M16209 and M16287 were effective in the prevention of galactosemic cataracts and amelioration of diabetic neuropathy with almost the same potency, while ONO-2235 was effective only in neuropathy, and sorbinil was effective in galactosemic cataracts and diabetic neuropathy with a different potency. These results indicate that M16209 and M16287 are potent aldose reductase inhibitors, which could be applicable to treatment for diabetic complications. 相似文献
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S Yokohama T Miwa S Aibara H Fujiwara H Matsumoto K Nakayama T Iwamoto M Mori R Moroi W Tsukada 《Chemical & pharmaceutical bulletin》1992,40(9):2391-2398
A series of 6-alkyl- or 6-(cycloalkylalkyl)-[1,3,4]thiadiazolo[3,2- a]-1,2,3-triazolo[4,5-d]pyrimidin-9(3H)-ones 1b--o was synthesized from the corresponding 1,3,4-thiadiazol-5-amines 3b--o and the antiallergic activities of the products were evaluated. Among the compounds 6-(2-cyclohexylethyl)- [1,3,4]thiadiazolo[3,2-a]-1,2,3-triazolo[4,5-d]pyrimidin-9(3H)-one 1h, whose X-ray crystallographic stereostructure is shown, was found to be a promising new antiallergic agent, which has low toxicity and dual activity as a leukotriene D4 receptor antagonist and as an orally active mast cell stabilizer. 相似文献
14.
Y Fukuyama M Kodama I Miura Z Kinzyo M Kido H Mori Y Nakayama M Takahashi 《Chemical & pharmaceutical bulletin》1989,37(2):349-353
Eckol (1), a novel phlorotannin with a dibenzo-1,4-dioxin skeleton, has been isolated from the brown alga Ecklonia kurome Okamura as a potent and specific anti-plasmin inhibitor. Its structure has been elucidated based on the spectral data, in particular, by means of negative nuclear Overhauser effect (NOE), and finally established as 1-(3,5-dihydroxyphenoxy)-2,4,7,9-tetrahydroxydibenzo-1,4-dio xin by X-ray analysis. Some partially methoxylated derivatives of eckol were prepared by methylation with diazomethane and also by selective dimethylation of eckol permethylate (1b) to establish the structural requirements for inhibitory activities on alpha 2-macroglobulin and alpha 2-plasmin inhibitor, the main plasmin inhibitors in plasma. 相似文献
15.
Protein profiling of rat cerebella during development 总被引:7,自引:0,他引:7
Protein profiles of developing rat cerebella were analyzed by means of two-dimensional gel electrophoresis (2-DE) and mass spectrometry (MS). The analysis of adult rat cerebellum gave rise to a protein map comprising approximately 3000 spots detectable by silver staining following high resolution 2-DE with a pH range of 3-10 and a mass range of 8-100 kDa. To obtain landmarks for comparison of developmental profiles of cerebellar proteins, 100 spots were subjected to peptide mass fingerprinting using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS), and 67 spots were assigned on the map. Analysis of profiles of the developing cerebella revealed significant changes in the expression of proteins during development. In most cases the expression levels of proteins increased as the cerebellum matured, while the expression of 42 spots appeared specific or remarkably abundant in the immature cerebellum. Peptide mass fingerprinting of these spots allowed us to identify 29 proteins, which include, in addition to proteins of unknown function, many proteins known to have roles in the development of the central nervous system. These results suggest that the proteomic approach is valuable for mass identification of proteins involved in cerebellar morphogenesis. 相似文献
16.
Balakin V Alexandrov VA Mikhailichenko A Flöttmann K Peters F Voss G Bharadwaj V Halling M Holt JA Buon J Jeanjean J LeDiberder F Lepeltier V Puzo P Heimlinger G Settles R Stierlin U Hayano H Ishihara N Nakayama H Oide K Shintake T Takeuchi Y Yamamoto N Bulos F Burke D Field R Hartman S Helm R Irwin J Iverson R Rokni S Roy G Spence W Tenenbaum P Wagner SR Walz D Williams S 《Physical review letters》1995,74(13):2479-2482
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Taisei Ueda Masumi Asahi Shin-Ichi Nagai Jinsaku Sakakibara 《Journal of heterocyclic chemistry》1996,33(1):169-172
Diazepinoquinoxalines 3, 4 and imidazolobenzopteridines 5, 6a-d, 7a-d, 8, 9 were synthesized from 3-allylamino-6,7-dimethyl-2-quinoxalinecarboxamide ( 1 ) and 2-allylamino-6,7-dimethyl-3,4-dihydrobenzo[g]pteridin-4-one ( 2 ) by the intramolecular cyclization using phenylselenenyl chloride. 相似文献
20.
Otani T Takayama J Sugihara Y Ishii A Nakayama J 《Journal of the American Chemical Society》2003,125(27):8255-8263
3,4-Di-tert-butylthiophene 1-oxide (1a) reacted with a series of electron-deficient alkenic dienophiles at its syn-pi-face relating to the S=O bond to give [4+2] adducts in excellent yields. The 1-oxide 1a also reacted even with angle-strained dienophiles acenaphthylene and norbornene at its syn-pi-face to afford [4+2] adducts; in the latter case, norbornene reacted exclusively at its exo-pi-face. The oxide 1a reacted with dimethyl acetylenedicarboxylate to produce dimethyl 4,5-di-tert-butylphthalate in high yield with spontaneous extrusion of SO from the initial adduct even at room temperature. Similarly, 3,4-di-tert-butylthiophene 1-(p-toluenesulfonyl)imide (3a) reacted with alkenic dienophiles at its syn-pi-face relating to the S=N bond to give [4+2] adducts in good yields. The reaction of 3a with 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD) afforded a 1,2-thiazetidine 12a, the first example of S-unoxidized 1,2-thiazetidine, in good yield, through rearrangement of the initial [4+2] adduct. The molecular structure of 12a is discussed on the basis of the X-ray crystallographic analysis. Comparison of the foregoing reactions leads to the conclusion that the 1-oxide 1a is more reactive as a diene than the 1-imide 3a, which is more reactive than 3,4-di-tert-butylthiophene 1,1-dioxide. The origin of the syn-pi-face selectivities of 1a and 3a in Diels-Alder reactions is discussed in terms of the orbital mixing rule and steric effect and also based on B3LYP/6-31G(d) calculations. 相似文献