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Masui H.,Yokohama University of Pharmacy | Yosugi S.,Yokohama University of Pharmacy | Fuse S.,Tokyo Institute of Technology | Takahashi T.,Yokohama University of Pharmacy
Beilstein Journal of Organic Chemistry | Year: 2017

A solution-phase automated synthesis of the versatile synthetic intermediate, Garner's aldehyde, was demonstrated. tert-Butoxycarbonyl (Boc) protection, acetal formation, and reduction of the ester to the corresponding aldehyde were performed utilizing our originally developed automated synthesizer, ChemKonzert. The developed procedure was also useful for the synthesis of Garner's aldehyde analogues possessing fluorenylmethyloxycarbonyl (Fmoc) or benzyloxycarbonyl (Cbz) protection. © 2017 Masui et al.; licensee Beilstein-Institut.


PubMed | Yokohama University of Pharmacy and Okayama University
Type: Journal Article | Journal: Xenobiotica; the fate of foreign compounds in biological systems | Year: 2016

1. Raloxifene is an antiestrogen that has been marketed for the treatment of osteoporosis, and is metabolized into 6- and 4-glucuronides by UDP-glucuronosyltransferase (UGT) enzymes. In this study, the in vitro glucuronidation of raloxifene in humans and monkeys was examined using liver and intestinal microsomes and recombinant UGT enzymes (UGT1A1, UGT1A8 and UGT1A9). 2. Although the K(m) and CL(int) values for the 6-glucuronidation of liver and intestinal microsomes were similar between humans and monkeys, and species differences in Vmax values (liver microsomes, humans>monkeys; intestinal microsomes, humansUGT1A8>UGT1A9 for humans, and UGT1A8>UGT1A1>UGT1A9 for monkeys. The activities of 4-glucuronidation were UGT1A8>UGT1A1>UGT1A9 in humans and monkeys. 4. These results demonstrated that the profiles for the hepatic and intestinal glucuronidation of raloxifene by microsomes were moderately different between humans and monkeys.


Fukuyama K.,Tohoku University | Ohrui H.,Tohoku University | Ohrui H.,Yokohama University of Pharmacy | Kuwahara S.,Tohoku University
Organic Letters | Year: 2015

An efficient enantioselective total synthesis of EFdA, a remarkably potent anti-HIV nucleoside analogue with various favorable pharmacological profiles, has been achieved in 37% overall yield from diacetone-d-glucose by a 14-step sequence that features a highly diastereoselective installation of the tetrasubstituted stereogenic center at the C4′ position, direct oxidative cleavage of an acetonide-protected diol derivative to an aldehyde, and one-pot 2′-deoxygenation of a ribonucleoside intermediate. © 2015 American Chemical Society.


Mukai M.,Okayama University | Isobe T.,Yokohama University of Pharmacy | Okada K.,Yokohama University of Pharmacy | Murata M.,Yokohama University of Pharmacy | And 2 more authors.
Pharmazie | Year: 2015

Propofol (2,6-diisopropylphenol) is a short-acting anesthetic commonly used in clinical practice, and is rapidly metabolized into glucuronide by UDP-glucuronosyltransferase (UGT). In the present study, propofol glucuronidation was examined in the liver microsomes of male and female humans, monkeys, rats, and mice. The kinetics of propofol glucuronidation by liver microsomes fit the substrate inhibition model for humans and mice, the Hill model for monkeys, and the isoenzyme (biphasic) model for rats. The Km, Vmax, and CLint values of human liver microsomes were 50μM, 5.6 nmol/min/mg protein, and 110μL/min/mg protein, respectively, for males, and 46μM, 6.0 nmol/min/mg protein, and 130μL/min/mg protein, respectively, for females. The rank order of the CLint or CLmax (in vitro clearance) values of liver microsomes was mice «humans > monkeys > rats (high-affinity phase)» rats (low-affinity phase) in both males and females. Although no significant sex differences were observed in the values of kinetic parameters in any animal species, the in vitro clearance values of liver microsomes were males < females in humans, males = females in rats (low-affinity phase), and males > females in monkeys, rats (high-affinity phase), and mice. These results demonstrated that the kinetic profile of propofol glucuronidation by liver microsomes markedly differed among humans, monkeys, rats, and mice, and suggest that species and sex differences exist in the roles of UGT isoform(s), including UGT1A9, involved in its metabolism.


PubMed | Yokohama University of Pharmacy, Meijo University and Okayama University
Type: Journal Article | Journal: Archives of toxicology | Year: 2016

Mono(2-ethylhexyl) phthalate (MEHP) is an active metabolite of di(2-ethylhexyl) phthalate (DEHP) and has endocrine-disrupting effects. MEHP is metabolized into glucuronide by UDP-glucuronosyltransferase (UGT) enzymes in mammals. In the present study, the hepatic and intestinal glucuronidation of MEHP in humans, dogs, rats, and mice was examined in an in vitro system using microsomal fractions. The kinetics of MEHP glucuronidation by liver microsomes followed the Michaelis-Menten model for humans and dogs, and the biphasic model for rats and mice. The K m and V max values of human liver microsomes were 110M and 5.8nmol/min/mg protein, respectively. The kinetics of intestinal microsomes followed the biphasic model for humans, dogs, and mice, and the Michaelis-Menten model for rats. The K m and V max values of human intestinal microsomes were 5.6M and 0.40nmol/min/mg protein, respectively, for the high-affinity phase, and 430M and 0.70nmol/min/mg protein, respectively, for the low-affinity phase. The relative levels of V max estimated by Eadie-Hofstee plots were dogs (2.0)>mice (1.4)>rats (1.0)humans (1.0) for liver microsomes, and mice (8.5)>dogs (4.1)>rats (3.1)>humans (1.0) for intestinal microsomes. The percentages of the V max values of intestinal microsomes to liver microsomes were mice (120%)>rats (57%)>dogs (39%)>humans (19%). These results suggest that the metabolic abilities of UGT enzymes expressed in the liver and intestine toward MEHP markedly differed among species, and imply that these species differences are strongly associated with the toxicity of DEHP.


PubMed | Yokohama University of Pharmacy
Type: Journal Article | Journal: Anticancer research | Year: 2016

Cancer cells tend to have a high requirement for lipids, including fatty acids, cholesterol and triglyceride, because of their rapid proliferative rate compared to normal cells. In this study, we investigated the effects of inhibition of lipid synthesis on the proliferation and viability of human pancreatic cancer cells. Of the inhibitors of lipid synthesis that were tested, 5-(tetradecyloxy)-2-furoic acid (TOFA), which is an inhibitor of acetyl-CoA carboxylase, and the fatty acid synthase (FAS) inhibitors cerulenin and irgasan, significantly suppressed the proliferation of MiaPaCa-2 and AsPC-1 cells. Treatment of MiaPaCa-2 cells with these inhibitors significantly increased the number of apoptotic cells. In addition, TOFA increased caspase-3 activity and induced cleavage of poly (ADP-ribose) polymerase in MiaPaCa-2 cells. Moreover, addition of palmitate to MiaPaCa-2 cells treated with TOFA rescued cells from apoptotic cell death. These results suggest that TOFA induces apoptosis via depletion of fatty acids and that, among the various aspects of lipid metabolism, inhibition of fatty acid synthesis may be a notable target for the treatment of human pancreatic cancer cells.


PubMed | Yokohama University of Pharmacy and Meijo University
Type: | Journal: Archives of toxicology | Year: 2016

4-tert-Octylphenol (4-tOP) is an endocrine-disrupting chemical. It is mainly metabolized into glucuronide by UDP-glucuronosyltransferase (UGT) enzymes in mammals. In the present study, the glucuronidation of 4-tOP in humans, monkeys, rats, and mice was examined in an in vitro system using microsomal fractions. The kinetics of 4-tOP glucuronidation by liver microsomes followed the Michaelis-Menten model for humans and monkeys, and the biphasic model for rats and mice. The K


PubMed | Yokohama University of Pharmacy and Hokuriku University
Type: | Journal: International journal of biological macromolecules | Year: 2016

Histones are intracellular proteins that are structural elements of nuclear chromatin and regulate gene transcription. However, the extracellular histones released in response to bacterial challenges have been identified as mediators contributing to endothelial dysfunction, organ failure, and death during sepsis. In the present study, the adsorption of histones as well as plasma proteins (1-acid glycoprotein (AGP), albumin, and -globulin) on alginic acid, pectin, dextran, and chitosan was examined in order to evaluate the potential of natural polysaccharides as therapeutic agents for multiple organ failure in sepsis. Alginic acid and pectin strongly adsorbed histones, whereas the adsorption abilities of dextran and chitosan toward histones were very low or negligible. Among the natural polysaccharides examined, only alginic acid did not adsorb any of the plasma proteins. These results demonstrated that alginic acid strongly adsorbed histones, but not plasma proteins; therefore, it has potential as a candidate drug for the treatment of multiple organ failure in sepsis.


PubMed | Yokohama University of Pharmacy, Meijo University and Okayama University
Type: | Journal: Archives of toxicology | Year: 2016

Mono(2-ethylhexyl) phthalate (MEHP) is an active metabolite of di(2-ethylhexyl) phthalate (DEHP), which is an endocrine-disrupting chemical. In the present study, MEHP glucuronidation in humans was studied using recombinant UDP-glucuronosyltransferases (UGTs) and microsomes of the liver and intestine. Among the recombinant UGTs examined, UGT1A3, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B4, and UGT2B7 glucuronidated MEHP. The kinetics of MEHP glucuronidation by UGT1A3, UGT1A7, UGT1A8, UGT1A10, UGT2B4, and UGT2B7 followed the Michaelis-Menten model, whereas that by UGT1A9 fit the negative allosteric model. CL


PubMed | Yokohama University of Pharmacy and Okayama University
Type: Journal Article | Journal: Xenobiotica; the fate of foreign compounds in biological systems | Year: 2016

1. UDP-glucuronosyltransferase 1A6 (UGT1A6) plays important roles in the glucuronidation of numerous drugs, environmental pollutants, and endogenous substances. Minipigs have been used as experimental animals in pharmacological and toxicological studies because many of their physiological characteristics are similar to those of humans. The aim of the present study was to examine similarities and differences in the enzymatic properties of UGT1A6 between humans and minipigs. 2. Minipig UGT1A6 (mpUGT1A6) cDNA was cloned by the RACE method, and the corresponding proteins were expressed in insect cells. The enzymatic function of mpUGT1A6 was analyzed by the kinetics of serotonin glucuronidation. 3. Amino acid homology between human UGT1A6 (hUGT1A6) and mpUGT1A6 was 79.9%. The kinetics of serotonin glucuronidation by recombinant hUGT1A6 and mpUGT1A6 enzymes fit the Michaelis-Menten equation. The Km, Vmax, and CLint values of hUGT1A6 were 10.5 mM, 4.04 nmol/min/mg protein, and 0.39 L/min/mg protein, respectively. The Km value of mpUGT1A6 was similar to that of hUGT1A6, whereas the Vmax and CLint values of mpUGT1A6 were approximately 2-fold higher than those of hUGT1A6. 4. These results suggest that the enzymatic properties of UGT1A6 enzymes are moderately different between humans and minipigs.

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