Biomedical subjects
Publications and source records attributed to A Matsuda.
A series of new purine nucleosides which have carbon substituents at their C-2 position were synthesized by non-aqueous diazotization/deamination of 2-amino-6-chloro-9-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)purine (1) with isoamyl nitrite in aromatic solvents and by palladium-catalyzed alkynylation of 2-iodo-adenosine (4) with terminal alkynes.
The antigenicity, local irritation and mutagenicity tests of bestatin (NK421) were carried out as special toxicity studies. The antigenicity tests in rabbits and guinea pigs were as follows: active and passive anaphylactic shock tests, Schultz-Dale reaction test, PCA (passive cutaneous anaphylaxis) reaction test, agar gel precipitation test, hemagglutination test of tannic acid-treated erythrocyte and the test according to the appraisal in the U.S.A. The ocular mucosal irritation test in rabbits was performed as a local irritation test. The mutagenicity test was made using S. typhimurium TA100, TA98 strains by means of preincubation method. The results were that NK421 had no antigenicity, irritation on the ocular mucosa and mutagenicity.
The first chemical synthesis of 3-methyl-psi-uridine (5) and its 2'-deoxy analogue (9) has been achieved. psi-Uridine was trimethylsilylated and the crude product was treated with acetyl chloride, to give the 1-acetyl derivative (3). Crude 3 was methylated with dimethoxymethyldimethylamine and then saponified, to give crystalline 5 in 82% overall yield. Treatment of 5 with 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane afforded the 3'5'-protected product, which was converted into the 2'O-[(imidazol-1-yl) thiocarbonyl] derivative 7. Reduction of 7 with tributyltin hydride followed by deblocking of the product gave crystalline 2'-deoxy-3-methyl-psi-uridine (9) in 35% yield form 5.
We measured the concentration in plasma of fibronectin, a recently characterized high molecular weight glycoprotein, in patients with various liver diseases. We found that it was significantly increased in acute hepatitis, fatty liver, all types of chronic hepatitis and liver cirrhosis without clinical evidence of ascites. Only in patients at the decompensated stage of liver cirrhosis, i.e. patients with clinical evidence of the presence of ascites, was it significantly reduced. Based on the immunohistochemical study on biopsy specimens of the liver using anti-human fibronectin antiserum, we suggest a possible correlation of the elevated plasma fibronectin to the wide distribution of specific fluorescence associated with the fibrillar structures in necrotic areas, expanded portal areas or thick fibrous septa in the liver diseases. Accelerated catabolism of plasma fibronectin mediated by increased fibrinolytic activity may contribute to the decrease in the level of plasma fibronectin in severe liver cirrhosis.
Family histories of diabetes mellitus in first-degree relatives were compared in Japanese patients with Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetes. The frequency of positive family histories for diabetes in first-degree relatives was 24% (13/55) in Type 1,44% (281/631) in Type 2 (p less than 0.01 versus Type 1) and 47% (16/34) when the type of diabetes could not be classified. The prevalence of diabetes in siblings of Type 2 patients was higher than in Type 1 diabetic patients (p less than 0.01). Patients with Type 2 diabetes and definite obesity in the past had a lower frequency of a family history of diabetes (p less than 0.01) and a lower prevalence of diabetes in their parents (p less than 0.01) than did Type 2 patients without obesity. The highest rate of family history for diabetes was observed in non-obese Type 2 diabetic patients of early onset. Our data agree with the previously known higher frequency of familial diabetes in Type 2 compared with Type 1 diabetes, despite the fact that there are significant dissimilarities between Type 1 diabetes in Japanese and Caucasoid population.
A beta-N-acetylhexosaminidase [EC 3.2.1.30] was isolated from internal organs of the sea-squirt, Styela plicata. The enzyme was purified 1,560-fold in 5% yield. The preparation was fairly homogeneous as examined by disc and SDS polyacrylamide gel electrophoresis and Sephadex G-200 chromatography. The molecular weight of the enzyme was estimated to be 132,000 by gel chromatography and 66,000 by SDS polyacrylamide gel electrophoresis. Therefore, this beta-N-acetylhexosaminidase was considered to be a dimer. The optimum pH for activity was 4.0 but the enzyme was stable in the pH range from 5 to 6. The isoelectric point was 4.99. This enzyme was inhibited by Fe2+, Hg2+, Ag+, and PCMB but not by acetate. The isolated enzyme hydrolyzed both p-nitrophenyl-N-acetyl-beta-D-glucosaminide and p-nitrophenyl-N-acetyl-beta-D-galactosaminide. The hydrolysis rate of p-nitrophenyl-N-acetyl-beta-D-galactosaminide was 43% of that of p-nitrophenyl-N-acetyl-beta-D-glucosaminide. The enzyme liberated N-acetylhexosamine from asialodegalactosyl ovomucoid glycopeptide, asialodegalactosyl fetuin glycopeptide and the fragment of hyaluronic acid prepared by hyaluronidase treatment.
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Therapeutic effects of PEP-AC and PEP-saline on pulmonary growth of intratracheally implanted tumor and metastasis into the hilar lymph nodes were studied in mice. Pharmacokinetic studies of PEP-AC and PEP-saline were made by autoradiography (ARG) using 3H-PEP and microbial assay method using B. subtilis. The ARG using 3H-PEP-AC and 3H-PEP-saline demonstrated qualitatively slower elimination of PEP-AC from mouse lung than that of PEP-saline. The half-life time (t1/2) of PEP-AC was estimated to be about 3 days by bioassay method, while about 60 min. was given for PEP-saline. Intratracheal administration of PEP-saline produced no therapeutic effect to pulmonary growth of B16 melanoma, while that of PEP-AC gave a good response depending on doses. Furthermore, PEP-AC inhibited metastasis of B16 melanoma into the hilar lymph nodes. Better therapeutic effects were produced by PEP-AC when decreased inoculum sizes of B16 melanoma or P388 leukemia cells were transplanted.
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Results of testing in mice and rats revealed that peplomycin has a stronger antitumor effect than bleomycin (BLM). Peplomycin, a BLM analogue, also has superior organ distribution characteristics and localizes in the rat prostate. Pulmonary toxicity associated with peplomycin therapy is less severe than that which accompanies BLM therapy.
5'-O-Glucuronides of anticancer nucleosides, 5-fluorouridine and 5-fluorocytidine, were synthesized by three different methods. The best preparative procedure was the one starting from benzyl 5-O-(methyl 2', 3', 4'-tri-O-acetyl-beta-D-glucopyranosyluronate)-2,3-O-isopropylidene-beta-D-ribof uranoside (15) that was obtained almost quantitatively by condensation of benzyl 2,3-O-isopropylidene-beta-D-ribofuranoside (8) with methyl (2,3,4-tri-O-acetyl-alpha-D-glucopyranosyl bromide)uronate (2). After de-O-isopropylidenation of 15, the crystalline product, benzyl 5-O-(methyl 2', 3', 4'-tri-O-acetyl-beta-D-glucopyranosyluronate)-beta-D-ribofuranoside (16), was de-O-benzylated catalytically to 5-O-(methyl 2', 3', 4'-tri-O-acetyl-beta-glucopyranosyluronate)-D-ribofuranose (17). Compound 17 was acetylated to crystalline 5-O-(methyl 2',3',4'-tri-O-acteyl-beta-D-glucopyranosyluronate)-1,2,3-tri-O-acetyl-beta-D-ribofuranose (18) and condensed with trimethylsilylated 5-fluorouracil of 5-fluorocytosine in the presence of SnCl4 to afford the corresponding protected nucleosides 5 and 19 in good yields. Saponification of these compounds gave 5'-O-beta-D-glucuronides of 5-fluorouridine and 5-fluorocytidine (20 and 21) isolated as their crystalline N salts. These glucuronides were substrates of both bacterial and bovine beta-glucuronidase. They were, as expected, much less toxic against several leukemia cell lines in tissue culture.
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5-Nitro-2'-deoxyuridylate (NO2dUMP) is a potent mechanism-based inhibitor of dTMP synthetase. After formation of a reversible enzymeìnhibitor complex, there is a rapid first order loss of enzyme activity which can be protected against by the nucleotide substrate dUMP. From studies of model chemical counterparts and the NO2dUMPdTMP synthetase complex, it has been demonstrated that a covalent bond is formed between a nucleophile of the enzyme and carbon 6 of NO2dUMP. The covalent NO2dUMPènzyme complex is sufficiently stable to permit isolation on nitrocellulose membranes, and dissociates to give unchanged NO2-dUMP with a first order rate constant of 8.9 x 10(-3) min-1. Dissociation of the complex formed with [6-3H]NO2dUMP shows a large alpha-secondary isotope effect of 19%, verifying that within the covalent complex, carbon 6 of the heterocycle is sp3-hybridized. The spectral changes which accompany formation of the NO2dUMPènzyme complex support the structural assignment and, when used to tritrate the binding sites, demonstrate that 2 mol of NO2dUMP are bound/mol of dimeric enzyme. The interaction of NO2dUMP with dTMP synthetase is quite different than that of other mechanism-based inhibitors such as 5-fluoro-2'-deoxyuridylate in that it neither requires nor is facilitated by the concomitant interaction of the folate cofactor, 5,10-CH2-H4folate, and that the covalent complex formed is unstable to protein denaturants.