Publications by authors named "Toshiaki Tsujino"

7 Publications

  • Page 1 of 1

Design, synthesis and evaluation of a novel cyclohexanamine class of neuropeptide Y Y1 receptor antagonists.

Bioorg Med Chem Lett 2009 Aug 17;19(16):4781-5. Epub 2009 Jun 17.

Tsukuba Research Institute, Merck Research Laboratories, Banyu Pharmaceutical Company, Ltd, 3 Okubo, Tsukuba 300-2611, Japan.

A novel series of cyclohexanamine derivatives was designed and synthesized as potent and selective human neuropeptide Y Y1 receptor antagonists. Modification of high-throughput screening hit compound 1 resulted in the identification of compound 3i, which displays potent Y1 activity and good selectivity towards hERG K(+) channel and serotonin transporter.
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http://dx.doi.org/10.1016/j.bmcl.2009.06.050DOI Listing
August 2009

Imidazopyridine derivatives as potent and selective Polo-like kinase (PLK) inhibitors.

Bioorg Med Chem Lett 2009 Aug 25;19(16):4673-8. Epub 2009 Jun 25.

Banyu Tsukuba Research Institute, Merck Research Laboratories, Banyu Pharmaceutical Co, Ltd, Tsukuba, Ibaraki 300-2611, Japan.

A novel class of imidazopyridine derivatives was designed as PLK1 inhibitors. Extensive SAR studies supported by molecular modeling afforded a highly potent and selective compound 36. Compound 36 demonstrated good antitumor efficacy in xenograft nude rat model.
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http://dx.doi.org/10.1016/j.bmcl.2009.06.084DOI Listing
August 2009

Optimization of a series of 2,4-diaminopyridines as neuropeptide Y Y1 receptor antagonists with reduced hERG activity.

Bioorg Med Chem Lett 2009 Aug 24;19(15):4325-9. Epub 2009 May 24.

Department of Medicinal Chemistry, Tsukuba Research Institute, Merck Research Laboratories, Banyu Pharmaceutical Co., Ltd, Okubo 3, Tsukuba, Ibaraki 300-2611, Japan.

The synthesis and evaluation of a series of 2,4-diaminopyridine-based neuropeptide Y Y1 (NPY Y1) receptor antagonists are described. Compound 1 was previously reported by our laboratory to be a potent and selective Y1 antagonist; however, 1 was also found to have potent hERG inhibitory activity. The main focus of this communication is structure-activity relationship development aimed at eliminating the hERG activity of 1. This resulted in the identification of compound 3d as a potent and selective NPY Y1 antagonist with reduced hERG liability.
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http://dx.doi.org/10.1016/j.bmcl.2009.05.069DOI Listing
August 2009

Detection of organic free radicals in irradiated Foeniculi fructus by electron spin resonance spectroscopy.

J Nat Med 2009 Jan 1;63(1):28-31. Epub 2008 Aug 1.

Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka, 569-1094, Japan.

Foeniculi fructus were irradiated with an electron beam and organic free radicals were detected by electron spin resonance (ESR) spectroscopy for the purpose of identifying radio-disinfected and sterilized herbal drugs. An ESR single-line spectrum near g = 2.005 was observed in the sample before irradiation. After irradiation, the intensity of the signal near g = 2.005 increased. In addition, two subsignals derived from cellulose radicals were observed approximately 3 mT to either side of the main signal, at g = 2.023 and g = 1.987. The intensity of the subsignal at g = 2.023 was proportional to the absorbed dose of radiation. The decrease in intensity of the signals was considerable 2 weeks after irradiation, and continued to decrease steadily thereafter. Among the signals, the fading of the subsignal at g = 2.023 was relatively small. The intensity of the subsignal at g = 2.023 was detectable for over 1 year in the sample that had been irradiated to the level of disinfection and sterilization. Therefore, organic free radicals in irradiated Foeniculi fructus can be measured rapidly and with high sensitivity by ESR spectroscopy. The stable signal at g = 2.023 is a promising indicator of the detection of irradiated herbal drugs.
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http://dx.doi.org/10.1007/s11418-008-0284-6DOI Listing
January 2009

Asymmetric total synthesis of fredericamycin A: an intramolecular cycloaddition pathway.

Chemistry 2005 Oct;11(21):6286-97

Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan.

The asymmetric total synthesis of the potent antitumor antibiotic fredericamycin A ((S)-1) was achieved by the intramolecular [4+2] cycloaddition of the silylene-protected styrene derivative (S)-7 followed by the aromatic Pummerer-type reaction of the sulfoxide (S)-5. Although we had already succeeded in the total synthesis of racemic 1 by the same approach, synthesis of its asymmetric version was more complicated than we had expected due to the difficulties involved in constructing the quaternary carbon center and the tendency of this center to undergo facile racemization. Racemization of this center during the installation of the acetylene moiety on the dione (R)-8 was the most serious aspect. Systematic studies of its DE-ring analogue (R)-25 revealed that racemization of the quaternary carbon center proceeded by a retro-aldol-aldol reaction of the initial adduct, (1R)-39 a-Li, and that the degree of racemization was dependent on the reaction temperature. The racemization process could be completely depressed by keeping the reaction temperature at -78 degrees C. The construction of the stereogenic quaternary carbon center was achieved by the lipase-catalyzed desymmetrization of the prochiral 1,3-diol 9 a bearing the DEF-ring moiety. These studies enabled us to attain the asymmetric total synthesis of (S)-1 while completely retaining the chiral integrity created by the enzymatic reactions.
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http://dx.doi.org/10.1002/chem.200500443DOI Listing
October 2005

Enantiodivergent preparation of optically active oxindoles having a stereogenic quaternary carbon center at the C3 position via the lipase-catalyzed desymmetrization protocol: effective use of 2-furoates for either enzymatic esterification or hydrolysis.

J Org Chem 2004 Apr;69(7):2478-86

Graduate School of Pharmaceutical Sciences, Osaka University, 1-6, Yamadaoka, Suita, Osaka 565-0871, Japan.

Both enantiomers of oxindoles 2a-h, having a stereogenic quaternary carbon center at the C3 position and a different N-protective group, were readily prepared by the lipase-catalyzed desymmetrization protocol. Thus, the transesterification of the prochiral diols 3a-h with 1-ethoxyvinyl 2-furoate 5 was catalyzed by Candida rugosa lipase to give (R)-(+)-2a-h (68-99% ee), in which the use of a mixed solvent, (i)Pr(2)O (diisopropyl ether)-THF, was crucial. The same lipase also effected the enantioselective hydrolysis of the difuroates 4a-h in a mixture of (i)Pr(2)O, THF, and H(2)O to provide the enantiomers (S)-(-)-2a-h (82-99% ee). The products 2 obtained by both methods were stable against racemization. These enzymatic desymmetrization reactions were also applicable for other typical symmetrical difuroates 12b and 15b to provide the racemization-resistant products 13b and 16b.
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http://dx.doi.org/10.1021/jo035749hDOI Listing
April 2004

Efficient lipase-catalyzed enantioselective desymmetrization of prochiral 2,2-disubstituted 1,3-propanediols and meso 1,2-diols using 1-ethoxyvinyl 2-furoate.

J Org Chem 2002 Jan;67(2):411-9

Graduate School of Pharmaceutical Sciences, Osaka University, Yamada-oka, Suita, Osaka 565-0871, Japan.

An efficient lipase-catalyzed desymmetrization of prochiral 2,2-disubstituted 1,3-propanediols was developed using 1-ethoxyvinyl 2-furoate 1b, for which the well-known method using vinyl or isopropenyl acetate has had limited success due to low reactivity and easy racemization of the products through acyl group migration. The reagent 1b is highly reactive and converts various prochiral 1,3-diols to the monoesters having a chiral quaternary carbon center with 82-99% ee. These products were stable against racemization under acidic conditions, and their furoyl groups were compatible with oxidative conditions. Prolonging the reaction time led to the kinetic resolution of the monoesters resulting in an increase of their optical purity. The similar desymmetrization of meso cis-1,2-cycloalkanediols gave the monoesters with 82-97% ee without racemization.
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http://dx.doi.org/10.1021/jo010587fDOI Listing
January 2002
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