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791.
Kawanaka Y Kobayashi K Kusuda S Tatsumi T Murota M Nishiyama T Hisaichi K Fujii A Hirai K Nishizaki M Naka M Komeno M Nakai H Toda M 《Bioorganic & medicinal chemistry》2003,11(5):689-702
The process of discovery and biological evaluation of alpha,beta-unsaturated cyclic amidines, as selective inhibitors of inducible nitric oxide synthase (iNOS), is reported. Dihydropyridin-2(1H)-imines and 1,5,6,7-tetrahydro-2H-azepin-2-imines were synthesized and biologically evaluated both in vitro and in vivo using a nitric oxide synthase inhibition assay. Compounds 1, 5, 6, 8-12 and 16 exhibited potent inhibition of iNOS. Among these, compounds 6, 7, 10, 11 and 16 showed 5- to 19-fold isoform selectivity. Compounds 1, 6, 10, 11 and 16 also showed potent inhibitory activity in the NOx accumulation assay in mice. Compounds 1 and 6 showed excellent bioavailability (BA) in rats when administered orally. Full details are presented here, including the structure-activity relationship (SAR) studies, the chemistry of these compounds, and the pharmacokinetic data and the computer-aided docking study of 10 with hiNOS. 相似文献
792.
The constitutional t(17;22): another translocation mediated by palindromic AT-rich repeats 总被引:13,自引:0,他引:13
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Kurahashi H Shaikh T Takata M Toda T Emanuel BS 《American journal of human genetics》2003,72(3):733-738
We have demonstrated that the breakpoints of the constitutional t(11;22) are located at palindromic AT-rich repeats (PATRRs) on 11q23 and 22q11. As a mechanism for this recurrent translocation, we proposed that the PATRR forms a cruciform structure that induces the genomic instability leading to the rearrangement. A patient with neurofibromatosis type 1 (NF1) had previously been found to have a constitutional t(17;22) disrupting the NF1 gene on 17q11. We have localized the breakpoint on 22q11 within the 22q11-specific low-copy repeat where the breakpoints of the constitutional t(11;22)s reside, implying a similar palindrome-mediated mechanism for generation of the t(17;22). The NF1 gene contains a 195-bp PATRR within intron 31. We have isolated the junction fragments from both the der(17) and the der(22). The breakpoint on 17q11 is close to the center of the PATRR. A published breakpoint of an additional NF1-afflicted patient with a constitutional t(17;22) is also located close to the center of the same PATRR. Our data lend additional support to the hypothesis that PATRR-mediated genomic instability can lead to a variety of translocations. 相似文献
793.
Misawa H Nakata K Toda K Matsuura J Oda Y Inoue H Tateno M Takahashi R 《Genesis (New York, N.Y. : 2000)》2003,37(1):44-50
The cholinergic gene locus (CGL) consists of the genes encoding the choline acetyltransferase (ChAT) and the vesicular acetylcholine transporter (VAChT). To establish a cholinergic-specific Cre-expressing mouse, we constructed a transgene expression vector (VAChT-Cre) with 11.3 kb human CGL in which a Cre-IRES-EGFP unit was inserted in the VAChT open reading frame. The activity of Cre, whose expression was driven by the VAChT promoter, was examined by crossing a reporter mouse (CAG-CAT-Z) in which expression of LacZ is activated upon Cre-mediated recombination. Transgenic lines with the VAChT-Cre construct displayed the restricted Cre expression in a subset of cholinergic neurons in the somatomotor nuclei and medial habenular nucleus, but absent in visceromotor and other central and peripheral cholinergic neurons. Cre expression was first observed at postnatal day 7 and later detected in approximately 40-60% of somatomotor neurons. Based on the onset of Cre expression, we generated two mouse lines (two alleles; VAChT-Cre. Fast and VAChT-Cre.Slow) in which Cre expression reaches maximal levels fast and slow, respectively. The use of VAChT-Cre mice should allow us to deliver Cre to a subset of postnatal motor neurons, thereby bypassing lethality and facilitating analysis of gene function in adult motor neurons. 相似文献
794.
Matsui T Kondo T Nishita Y Itadani S Tsuruta H Fujita S Omawari N Sakai M Nakazawa S Ogata A Mori H Ohno H Obata T Nakai H Toda M 《Bioorganic & medicinal chemistry letters》2002,12(6):907-910
Metabolic stabilization of the chemical lead 1, which is a structurally novel inhibitor of TNF-alpha production, was accomplished by introducing a (1S)-methyl group into the optically active backbone. As a result, 2, 3 and 4 were identified as drug candidates and evaluated pharmacologically. The analysis of an active conformer was also carried out. 相似文献
795.
Matsui T Kondo T Nishita Y Itadani S Nakatani S Omawari N Sakai M Nakazawa S Ogata A Mori H Terai K Kamoshima W Ohno H Obata T Nakai H Toda M 《Bioorganic & medicinal chemistry》2002,10(12):3757-3786
Discovery of new chemical leads of inhibitors for TNF-alpha production starting from the chemical modification of 1 is reported. Further biological studies of 1 to disclose the site of its action strongly suggested that 1 inhibits LPS-induced TNF-alpha expression in the liver and spleen of mice. Structure-activity relationships (SARs) are also discussed and full details including the chemistry are reported. 相似文献
796.
A fourth component of the fission yeast gamma-tubulin complex,Alp16, is required for cytoplasmic microtubule integrity and becomes indispensable when gamma-tubulin function is compromised
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gamma-Tubulin functions as a multiprotein complex, called the gamma-tubulin complex (gamma-TuC), and composes the microtubule organizing center (MTOC). Fission yeast Alp4 and Alp6 are homologues of two conserved gamma-TuC proteins, hGCP2 and hGCP3, respectively. We isolated a novel gene, alp16(+), as a multicopy suppressor of temperature-sensitive alp6-719 mutants. alp16(+) encodes a 759-amino-acid protein with two conserved regions found in all other members of gamma-TuC components. In addition, Alp16 contains an additional motif, which shows homology to hGCP6/Xgrip210. Gene disruption shows that alp16(+) is not essential for cell viability. However, alp16 deletion displays abnormally long cytoplasmic microtubules, which curve around the cell tip. Furthermore, alp16-deleted mutants are hypersensitive to microtubule-depolymerizing drugs and synthetically lethal with either temperature-sensitive alp4-225, alp4-1891, or alp6-719 mutants. Overproduction of Alp16 is lethal, with defective phenotypes very similar to loss of Alp4 or Alp6. Alp16 localizes to the spindle pole body throughout the cell cycle and to the equatorial MTOC at postanaphase. Alp16 coimmunoprecipitates with gamma-tubulin and cosediments with the gamma-TuC in a large complex (>20 S). Alp16 is, however, not required for the formation of this large complex. We discuss evolutional conservation and divergence of structure and function of the gamma-TuC between yeast and higher eukaryotes. 相似文献
797.
798.
Skp1 is a core component of the Skp1-Cullin-1-F-box ubiquitin ligase. Here, we show a novel role for fission yeast Skp1 in mitotic progression. Temperature-sensitive skp1-A7 mutants enter mitosis, but fail to execute anaphase. Time-lapse imaging shows that spindles in this mutant form intranuclear arch-like structures, which eventually collapse abruptly. The two spindle poles are also seen to move backward to the cell centre rather than towards the cell ends. These abnormal phenotypes appear to stem from defects in nuclear membrane segregation. Our results show that Skp1 is required for coordinated structural alterations of mitotic spindles and nuclear membranes. 相似文献
799.
Microtubules display dramatic morphological alterations from mitotic spindles to fibrous interphase structures upon exit from mitosis. In this issue of Developmental Cell, Zimmerman et al. shed a novel light on the molecular mechanism of microtubule structure reorganization during cytokinesis. 相似文献
800.
Inhibitory effects of ellagi- and gallotannins on rat intestinal alpha-glucosidase complexes 总被引:4,自引:0,他引:4
The clove ellagitannins and their related polygalloyl-glucoses inhibited maltase activity of rat intestinal alpha-glucosidases. The structure-activity relationship study of those galloylglucoses, varying the extent of galloylation on the glucose core, with the ellagitannins, indicated that an increasing number of galloyl units in the molecule lead to an increase in the inhibitory activity. Penta-O-galloyl-beta-D-glucose, with five galloyl groups showed the highest inhibitory activity. On the other hand, hexahydroxydiphenoyl units contained in the ellagitannins had little effect on the activity. After separation of maltase-glucoamylase and sucrase-isomaltase complexes from the crude mixture of the rat alpha-glucosidases, the inhibitory activities of the galloylglucose derivatives against each complex were examined. The inhibitory influence on the maltase-glucoamylase complex was more potent than on the sucrase-isomaltase complex. 相似文献