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121.
Shelton JR Cutler CE Oliveira M Balzarini J Peterson MA 《Bioorganic & medicinal chemistry》2012,20(2):1008-1019
We have developed efficient methods for the preparation of N(6),5'-bis-ureidoadenosine derivatives and their 5'-carbamoyl-N(6)-ureido congeners. Treatment of 5'-azido-5'-deoxy-N(6)-(N-alkyl or -arylurea)adenosine derivatives (6a-d) with H(2)/Pd-C or Ph(3)P/H(2)O, followed by N-methyl-p-nitrophenylcarbamate gave N(6),5'-bis-ureido products 7a-d in 49-78% yield. Analogous derivatives in the 5'-carbamoyl-N(6)-ureido series were prepared by treatment of 2',3'-bis-O-TBS-adenosine (11) with N-methyl-p-nitrophenylcarbamate followed by acylation with appropriate isocyanates which gave 13a-d in 45-69% yield. A more versatile route for obtaining potentially vast libraries of compounds from both series was achieved by treatment of 5'-N-methylureido- or 5'-N-methylcarbamoyladenosine derivatives with ethylchlorformate to give N(6)-ethoxycarbonyl derivatives (9 and 14) in 55-63% yields, respectively. Simple heating of 9 or 14 in the presence of primary alkyl- or arylamines gave the corresponding N(6),5'-bis-ureido- or 5'-carbamoyl-N(6)-ureidoadenosine derivatives in good yields (33-72% and 39-83%; 10a-e and 15a-e, respectively). Significant antiproliferative activities (IC(50)≈4-10 μg/mL) were observed for a majority of the N(6),5'-bis-ureido derivatives, whereas the 5'-carbamoyl-N(6)-ureido derivatives were generally less active (IC(50) >100 μg/mL). A 2',3'-O-desilylated derivative (5'-amino-5'-deoxy-5'-N-methylureido-N(6)-(N-phenylcarbamoyl)adenosine, 16) was shown to inhibit binding of 16 of 441 protein kinases to immobilized ATP-binding site ligands by 30-40% in a competitive binding assay at 10 μM. Compound 16 was also shown to bind to bone morphogenetic protein receptor 1b (BMPR1b) with a Kd=11.5 ± 0.7 μM. 相似文献
122.
Iron deficiency (ID) remains a public health concern affecting ~25% of the world’s population. Metabolic consequences of ID include elevated plasma glucose concentrations consistent with increased reliance on glucose as a metabolic substrate, though the mechanisms controlling these responses remain unclear. To further characterize the metabolic response to ID, weanling male Sprague–Dawley rats were fed either a control (C; 40 mg Fe/kg diet) or iron-deficient (ID; 3 mg Fe/kg diet) diet or were pair-fed (PF) the C diet to the level of intake of the ID group for 21 days. In addition to reductions in hemoglobin, hematocrit, and plasma iron, the ID group also exhibited higher percent body fat and plasma triglycerides compared to the PF group. Steady-state levels of both plasma glucose and insulin increased 40 and 45%, respectively, in the ID group compared to the PF group. Plasma cortisol levels were decreased 67% in the ID group compared to the PF diet group. The systematic evaluation of the expression of genes involved in insulin signaling, glucose metabolism, and fatty acid metabolism in the liver and skeletal muscle revealed significant alterations in the expression of 48 and 52 genes in these tissues, respectively. A significant concurrent increase in lipogenic gene expression and decrease in gene expression related to β-oxidation in both the liver and skeletal muscle, in combination with differential tissue expression of genes involved in glucose metabolism, provides novel insight into the adaptive metabolic response in rodent models of severe iron deficiency anemia. 相似文献
123.
Peterson RT Shaw SY Peterson TA Milan DJ Zhong TP Schreiber SL MacRae CA Fishman MC 《Nature biotechnology》2004,22(5):595-599
Conventional drug discovery approaches require a priori selection of an appropriate molecular target, but it is often not obvious which biological pathways must be targeted to reverse a disease phenotype. Phenotype-based screens offer the potential to identify pathways and potential therapies that influence disease processes. The zebrafish mutation gridlock (grl, affecting the gene hey2) disrupts aortic blood flow in a region and physiological manner akin to aortic coarctation in humans. Here we use a whole-organism, phenotype-based, small-molecule screen to discover a class of compounds that suppress the coarctation phenotype and permit survival to adulthood. These compounds function during the specification and migration of angioblasts. They act to upregulate expression of vascular endothelial growth factor (VEGF), and the activation of the VEGF pathway is sufficient to suppress the gridlock phenotype. Thus, organism-based screens allow the discovery of small molecules that ameliorate complex dysmorphic syndromes even without targeting the affected gene directly. 相似文献
124.
William A Baumgartner Amanda J Peterson Robert G Presson Nobuhiro Tanabe Eric M Jaryszak Wiltz W Wagner 《Journal of applied physiology》2004,97(2):522-526
Pulmonary capillary perfusion within a single alveolar wall continually switches among segments, even when large-vessel hemodynamics are constant. The mechanism is unknown. We hypothesize that the continually varying size of plasma gaps between individual red blood cells affects the likelihood of capillary segment closure and the probability of cells changing directions at the next capillary junction. We assumed that an increase in hematocrit would decrease the average distance between red blood cells, thereby decreasing the switching at each capillary junction. To test this idea, we observed 26 individual alveolar capillary networks by using videomicroscopy of excised canine lung lobes that were perfused first at normal hematocrit (31-43%) and then at increased hematocrit (51-62%). The number of switches decreased by 38% during increased hematocrit (P < 0.01). These results support the idea that a substantial part of flow switching among pulmonary capillaries is caused by the particulate nature of blood passing through a complex network of tubes with continuously varying hematocrit. 相似文献
125.
Fatty acid monooxygenation by cytochrome P-450BM-3 总被引:8,自引:0,他引:8
S S Boddupalli R W Estabrook J A Peterson 《The Journal of biological chemistry》1990,265(8):4233-4239
Cytochrome P-450BM-3 is a catalytically self-sufficient enzyme which monooxygenates saturated and unsaturated fatty acids, alcohols, and amides. The protein has two domains: one which contains heme and is P-450-like and the other which contains FAD and FMN and is P-450 reductase-like. Both domains are on a single polypeptide chain. Utilizing a plasmid containing the gene encoding P-450BM-3, we have transformed the Escherichia coli strain DH5 alpha. This clone overexpresses P-450BM-3 to make approximately 20% of the soluble protein of this organism under optimal conditions. P-450BM-3 can be purified to homogeneity from the soluble fraction of the protein of these cells with a recovery of 50% making this cell line an excellent source of this important enzyme. Purified preparations of P-450BM-3 hydroxylate palmitic acid at a rate of 1600 mol/min/mol of heme at 25 degrees C. The stoichiometry of NADPH to oxygen utilized was 1 for all conditions; however, the ratio of oxygen or NADPH utilized per molecule of fatty acid substrate metabolized was different for different homologs of saturated fatty acids, when low concentrations (less than 100 microM) of substrate were used. Lauric and myristic acids were metabolized to two hydroxylated products, irrespective of the initial concentration of fatty acid in the reaction mixture, and the ratio of oxygen consumed to fatty acid hydroxylated was 1. High concentrations of palmitic acid (greater than 200 microM) led to the formation of three polar metabolites and a stoichiometry of 1:1 was observed for oxygen and palmitic acid utilization. These results indicate that a single hydroxyl group was inserted into each of these molecules. Lower concentrations (less than 50 microM) of palmitic acid were metabolized to additional polar metabolites, and the ratio of oxygen consumed to fatty acid substrate consumed approximated 3:1. These results can be explained best by a hypothesis that the initial hydroxylated compounds, which accumulate during the oxidation of palmitic acid by P-450BM-3, can be further oxidized by this enzyme to polyhydroxy- or hydroxy-ketone products. 相似文献
126.
Peterson SA 《Journal of biosocial science》1999,31(1):93-104
Analysis of the 1992 Niger Demographic and Health Survey showed that although roughly two-thirds of both polygamous and monogamous women approve of birth control, polygamous wives are less likely than monogamous wives to discuss family size or birth control with their husband or to plan on using birth control. The study suggests that characteristics of polygamous couples have caused polygamous women to be more resistant to birth control use than monogamous women. The polygamous women tended to be married to older men who had not gone to primary school and who desired more children than monogamous husbands. The influence of marital structure is not significantly associated with intention to use birth control when the husband's age and the wife's ideal number of children were controlled for in the multivariate logistic regression model suggesting that background social factors may be more influential. In fact, educational level and age at first marriage were significantly associated with attitudes towards birth control and also with marital structure. 相似文献
127.
Egg production rates of eight calanoid copepod species during summer 1997 off Newport, Oregon, USA 总被引:3,自引:0,他引:3
Measurements of hydrography, water transparency, chlorophyll (Chl)
a and egg production rates (EPRs) by females of
Calanus marshallae Frost, Calanus
pacificus Brodsky, Eucalanus californicus
Johnson, Epilabidocera longipedata Sato,
Pseudocalanus mimus Frost, Centropages
abdominalis Sato, Acartia longiremis
Lilljerborg and Paracalanus parvus (Claus) were
estimated at weekly intervals between 17 July and 2 September 1997.
Production of eggs was determined in 24 h incubations to examine the
effects of environmental variability on EPR, to detect the possibility of
food limitation of EPR, and to evaluate the hypothesis that growth rates of
females are size dependent. During the study, an anomalous downwelling
event occurred, possibly in response to the 1997 El Niño, which
allowed us to determine how El Niño events affect EPRs of
coastal copepods. The larger copepods Calanus marshallae, Calanus
pacificus and Centropages abdominalis
showed the highest egg production and specific growth rates during the
period of active upwelling (18 July-13 August, water temperatures
8-13C, Chl a
concentration 4.7-16.2
l-1 and water transparency 3-5 m). After 27 August,
the 1997-98 El Niño arrived off Oregon, creating a downwelling
situation. Upwelling winds ceased, the thermocline intensified, temperature
and transparency increased (to >18°C and 16 m), and Chl
a declined to <2 g
l-1. Densities of the common coastal species
declined greatly as well. Paracalanus parvus became
the dominant species, and Eucalanus californicus, Epilabidocera
longipedata and Corycaeus anglicus became
common in our samples. EPRs for the larger boreal copepods
(Calanus and Centropages)
declined greatly during El Niño;; the smaller copepods,
Pseudocalanus mimus, A.longiremis and
Paracalanus parvus, showed low but relatively constant
egg production and specific growth rates during both upwelling and
downwelling events. Over the entire study period, only three species
produced eggs at its maximum rate (24-28 eggs
female-1 day-1),
Pseudocalanus mimus which averaged 4 eggs
day-1. All other species had EPRs that were two or
five times below their maximum EPR. Thus, EPRs were not related to body
size, contrary to our expectations. Hatching success was variable among
species. Values as low as 20-40% were found for all species at least once
during the study period, suggesting that occasionally a substantial portion
of egg production may not be viable.
相似文献
128.
129.
Human microvascular endothelial cell prostaglandin E1 synthesis during in vitro ischemia-reperfusion
Watkins MT Al-Badawi H Russo AL Soler H Peterson B Patton GM 《Journal of cellular biochemistry》2004,92(3):472-480
Ischemia-reperfusion injury is a microvascular event documented in numerous in vivo animal models. In animal models, prostaglandin and prostaglandin analogues have been found to ameliorate reperfusion injury. These studies were undertaken to evaluate human microvascular endothelial PGE(1) synthesis during in vitro ischemia followed by reperfusion. Human (neonatal) microvascular endothelial cell (MEC) cultures (n = 6) were subjected to sequential 2 h periods of normoxia (20% O(2)), ischemia (1.5% O(2)), and reperfusion (20% O(2)). Prostaglandin E(2) synthesis in conditioned media was determined by ELISA. Steady state levels of MEC prostaglandin H synthase (PGHS)-1 and -2 mRNA were assessed at the end of each 2-h period using RT-PCR and a quantitative mRNA ELISA. MEC PGHS protein levels were analyzed using an ELISA. PGE(1) release increased significantly during the initial 30 min of ischemia, but rapidly fell below normoxic levels by 90 and 120 min. During reperfusion, PGE(1) release returned to normoxic levels at 30, 60, and 90 min, and exceeded normoxic levels at 120 min. PGHS-1 mRNA levels were undetectable during all experimental conditions. PGHS-2 mRNA levels were unchanged by ischemia, but were decreased by reperfusion. In contrast, PGHS-2 protein levels increased 3-fold during ischemia, and remained elevated during reperfusion. Human MEC do not express PGHS-1 mRNA in vitro. Prolonged ischemia decreases MEC PGE(1) synthesis, and stimulates increased PGHS-2 protein levels without altering the steady state levels of COX-2 mRNA. During reperfusion, increased PGHS-2 protein levels persist and are associated with stimulated PGE(2) secretion, despite relative decreases in PGHS-2 mRNA. 相似文献
130.
Martínez-Meyer E Peterson AT Navarro-Sigüenza AG 《Proceedings. Biological sciences / The Royal Society》2004,271(1544):1151-1157
The evolution of migration has long been considered complex and recent work has demonstrated additional complexity: some species follow the same ecological conditions throughout the year, whereas others 'switch niches' between breeding and wintering ranges. Hypotheses regarding the evolution of migration would generally predict niche-following as primitive, and niche-switching as derived. However, no test has, to our knowledge, yet determined the directionality of evolution of these states within a lineage. We present an analysis of phylogenetic dimensions of seasonal niches in the Passerina buntings that indicates greater evolutionary change in the niches of breeding populations than among those of wintering populations. These results are consistent with hypotheses of (i) niche conservatism (in winter, at least) across a recently speciated lineage; and (ii) the derived state of the breeding (rather than winter) ecological niches of each species. 相似文献