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41.
Margaret C. Ackley Colin G. Barry Amanda M. Mounce Michael C. Farmer Beth-Erin Springer Cynthia S. Day Marcus W. Wright Susan J. Berners-Price Suzanne M. Hess Ulrich Bierbach 《Journal of biological inorganic chemistry》2004,9(4):453-461
The synthesis, cytotoxicity, and nucleoside binding of some platinum–acridinylthiourea conjugates derived from the prototypical compound [PtCl(en)(ACRAMTU)](NO3)2 {PT-ACRAMTU; en=ethane-1,2-diamine, ACRAMTU=1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea, protonated form} are reported. To establish structure–activity relationships within this class of compounds, systematic changes were made to the thiourea nonleaving group, which links the intercalator to platinum. Three new derivatives of ACRAMTU, one di-, one tri-, and one tetraalkylated, were generated, where the degree of alkylation indicates the number of alkyl groups attached to the SCN2 framework. Subsequent reaction of the tri- and tetraalkylated derivatives with activated [PtCl2(en)] yielded the corresponding platinum conjugates. The dialkylated thiourea gave an unstable complex, which was not included in the studies. The crystal structure of PT-ACRAMTU·MeOH has been determined. In the solid state, one axial position of the square-planar platinum coordination sphere is partially shielded by the bulky thiourea group, providing a strong rationale for the kinetic inertness of the compound. The cytotoxicity of the prototype, the two new conjugates, and cisplatin was assessed in ovarian (A2780, A2780/CP), lung (NCI-H460), and colon (RKO) cancer cell lines using clonogenic survival assays. The derivatives containing trialkylated thiourea groups showed activity similar or superior to cisplatin, with IC50 values in the low micromolar concentration range. The complex modified with the tetraalkylated (bulkiest) thiourea was significantly less active, possibly due to the greatly decreased rate of binding to nucleobase nitrogen (1H NMR spectroscopy), but was most efficient at overcoming cross resistance to cisplatin in A2780/CP. Possible consequences of the reported structural modifications for the mechanism of action of these agents are discussed.Electronic Supplementary Material Supplementary material is available in the online version of this article at Abbreviations ACRAMTU 1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea - Boc t-butyl carbamate - dGuo 2-deoxyguanosine - dien N1-(2-aminoethyl)ethane-1,2-diamine - en ethane-1,2-diamine - HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid - PT-ACRAMTU [PtCl(en)(ACRAMTU)](NO3)2 - TSP 3-(trimethylsilyl)propionate, sodium salt 相似文献
42.
Sawkins MC Farmer AD Hoisington D Sullivan J Tolopko A Jiang Z Ribaut JM 《Plant molecular biology》2004,56(3):465-480
In the past few decades, a wealth of genomic data has been produced in a wide variety of species using a diverse array of functional and molecular marker approaches. In order to unlock the full potential of the information contained in these independent experiments, researchers need efficient and intuitive means to identify common genomic regions and genes involved in the expression of target phenotypic traits across diverse conditions. To address this need, we have developed a Comparative Map and Trait Viewer (CMTV) tool that can be used to construct dynamic aggregations of a variety of types of genomic datasets. By algorithmically determining correspondences between sets of objects on multiple genomic maps, the CMTV can display syntenic regions across taxa, combine maps from separate experiments into a consensus map, or project data from different maps into a common coordinate framework using dynamic coordinate translations between source and target maps. We present a case study that illustrates the utility of the tool for managing large and varied datasets by integrating data collected by CIMMYT in maize drought tolerance research with data from public sources. This example will focus on one of the visualization features for Quantitative Trait Locus (QTL) data, using likelihood ratio (LR) files produced by generic QTL analysis software and displaying the data in a unique visual manner across different combinations of traits, environments and crosses. Once a genomic region of interest has been identified, the CMTV can search and display additional QTLs meeting a particular threshold for that region, or other functional data such as sets of differentially expressed genes located in the region; it thus provides an easily used means for organizing and manipulating data sets that have been dynamically integrated under the focus of the researchers specific hypothesis. 相似文献
43.
Perni RB Pitlik J Britt SD Court JJ Courtney LF Deininger DD Farmer LJ Gates CA Harbeson SL Levin RB Lin C Lin K Moon YC Luong YP O'Malley ET Rao BG Thomson JA Tung RD Van Drie JH Wei Y 《Bioorganic & medicinal chemistry letters》2004,14(6):1441-1446
The alpha-ketoamide warhead (e.g., 15) was found to be a practical replacement for aliphatic aldehydes in a series of HCV NS3.4A protease inhibitors. Structure-activity relationships and prime side optimization are discussed. 相似文献
44.
A conserved transcript pattern in response to a specialist and a generalist herbivore 总被引:24,自引:0,他引:24
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Reymond P Bodenhausen N Van Poecke RM Krishnamurthy V Dicke M Farmer EE 《The Plant cell》2004,16(11):3132-3147
45.
Synaptosomes, isolated from the whole brain of young (3 months) and old (24 months) rats were used to study the major bioenergetic systems of neuronal mitochondria in situ, within the synaptosome. Approximately 85% of the resting oxygen consumption of synaptosomes from both young and old rats was a result of proton leak (and possibly other ion cycling) across the mitochondrial inner membrane. There were no significant differences between synaptosomes from the young and old rats in the kinetic responses of the substrate oxidation system, the mitochondrial proton leak and the phosphorylation system to changes in the proton electrochemical gradient. Flux control coefficients of 0.71, 0.27 and 0.02 were calculated for substrate oxidation system, phosphorylation system and the proton leak, respectively, at maximal ATP producing capacity in synaptosomes from young animals. The corresponding values calculated for synaptosomes from old animals were 0.53, 0.43 and 0.05. Thus substrate oxidation had greatest control over oxygen consumption at maximal phosphorylating capacity for synaptosomes from whole brain, with proton leak, having little control under maximal ATP producing capacity. The uncoupled rate of oxygen consumption, in the presence of the mitochondrial uncoupler, carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP), was significantly lower (p = 0.0124) in synaptosomes from old rats (6.08 +/- 0.42, n = 11) when compared with those from the young rats (7.87 +/- 0.48, n = 8). Thus, there is an impaired flux through the substrate oxidation system is synaptosomes from old rats, as compared to synaptosomes from the young animals. These in situ results may have important implications for the interpretation of theories that age-dependent impairment of mitochondrial energy production may result in increased susceptibility to neurodegeneration. 相似文献
46.
Liu C Eriste E Sutton S Chen J Roland B Kuei C Farmer N Jörnvall H Sillard R Lovenberg TW 《The Journal of biological chemistry》2003,278(50):50754-50764
GPCR135, publicly known as somatostatin- and angiotensin-like peptide receptor, is expressed in the central nervous system and its cognate ligand(s) has not been identified. We have found that both rat and porcine brain extracts stimulated 35S-labeled guanosine 5'-O-(3-thiotriphosphate) (GTPgammaS) incorporation in cells over-expressing GPCR135. Multiple rounds of extraction, purification, followed by N-terminal sequence analysis of the ligand from porcine brain revealed that the ligand is a product of the recently identified gene, relaxin-3 (aka insulin-7 or INSL7). Recombinant human relaxin-3 potently stimulates GTPgammaS binding and inhibits cAMP accumulation in GPCR135 overexpressing cells with EC50 values of 0.25 and 0.35 nM, respectively. 125I-Relaxin-3 binds GPCR135 at high affinity with a Kd value of 0.31 nM. Relaxin-3 is the only member of the insulin/relaxin superfamily that can activate GPCR135. In situ hybridization showed that relaxin-3 mRNA is predominantly expressed in the dorsomedial ventral tegmental nucleus of the brainstem (aka nucleus incertus), as well as in discrete cells in the lateral periaqueductal gray and in the central gray nucleus. GPCR135 is expressed abundantly in the hypothalamus with discrete expression in the paraventricular nucleus of the hypothalamus and supraoptic nucleus, as well as in the cortex, septal nucleus, and preoptical area. Relaxin-3 has previously been shown to bind and activate the LGR7 relaxin receptor. However, we believe that neuroanatomical colocalization of GPCR135 and relaxin-3, coupled with a clear high affinity interaction, suggest that GPCR135 is the receptor for relaxin-3. The identification of relaxin-3 as the ligand for GPCR135 provides the framework for the discovery of a new brainstem/hypothalamus circuitry. 相似文献
47.
48.
Pleiotropic effects of statins: do they matter? 总被引:7,自引:0,他引:7
Treatment with the 3-hydroxy-3-methylglutaryl coenyzme A reductase inhibitors (or statins) reduces the risk for cardiovascular events across a broad spectrum of patient profiles, as evidenced by both primary prevention and secondary prevention trials. Improved survival by way of reduced deaths from coronary heart disease was also reported with these agents, which are primarily indicated for substantial reduction in LDL-cholesterol levels. However, the statins are extremely complex drugs and exhibit a wide variety of vascular effects that may or may not be dependent on their lipid-modifying properties. These so-called pleiotropic effects include alterations of endothelial function, inflammation, coagulation, and plaque stability. The relative contribution of the nonlipid effects of statin therapy to the well-documented clinical benefits is currently under intense investigation. 相似文献
49.
Borchers MT Crosby J Farmer S Sypek J Ansay T Lee NA Lee JJ 《American journal of physiology. Lung cellular and molecular physiology》2001,280(4):L813-L821
Lymphocyte and/or eosinophil recruitment is dependent on the sequential interactions between adhesion molecules expressed on activated endothelial cells and both leukocyte subtypes. Endothelial P- and E-selectins mediate tethering and rolling of leukocytes through interactions with P-selectin glycoprotein ligand-1 (PSGL-1), and diapedesis subsequently occurs by engagement of endothelial vascular cell adhesion molecule-1 and CD49d (alpha(4)-integrins). The anti-inflammatory potential of interfering with these adhesive interactions was assessed with an ovalbumin challenge mouse model of asthma. Administration of a soluble form of PSGL-1 reduced eosinophils (80%) and lymphocytes (50%) in bronchoalveolar lavage fluid without affecting epithelial changes or airway hyperreactivity (AHR). In contrast, although administration of anti-CD49d monoclonal antibodies (PS/2) resulted in similar reductions in eosinophils (75%) and lymphocytes (50%), PS/2 reduced and abolished mucous cell metaplasia and AHR, respectively. Administration of both PSGL-1 and PS/2 had the additive effect of eliminating eosinophils from the airways (96% decrease), with few or no additional reductions (relative to PS/2 administration alone) in lymphocyte recruitment, mucous cell metaplasia, or AHR. These data show that eosinophils and lymphocytes differentially utilize adhesive interactions during recruitment and that the inhibition of AHR is independent of this recruitment. 相似文献
50.
Farmer KH 《American journal of primatology》2002,58(3):117-132
While wild populations continue to decrease, the number of orphaned primates, sanctuaries, and attempts to reintroduce primates back to the natural environment are increasing. An umbrella organization called the Pan-African Sanctuary Alliance (PASA) was formed in 2000 and recently the IUCN Reintroduction Specialist Group developed a set of specific policy guidelines for primates (2002). Data presented in this report are based upon questionnaire responses by managers from 17 African facilities that have become members of PASA (membership in PASA is defined by attendance at an annual PASA workshop). These PASA facilities house over 500 great apes. (There may be other facilities not represented here simply because their managers did not attend a PASA workshop.) The majority of the apes arrived at the sanctuaries when they were less than 4 years old and half were confiscated. Over 40% were found awaiting sale, and 30% had been previously kept as pets. Common ailments upon arrival included internal parasites, behavioral abnormalities, and malnutrition; 20% of the total sanctuary population died prematurely. Most sanctuaries use a combination of enclosures surrounded by electric fencing and cages to accommodate the apes. Sanctuaries actively participate in conservation education, habitat protection, tourism, scientific data collection, local development, and reintroduction. The median total facility operating cost was 65,000 US dollars per annum. The median facility cost per ape was 2,222 US dollars per annum. Most funding comes from overseas nongovernmental agencies. Discussion focuses on evaluating the present status of sanctuaries, the problems facing them, and their potential role in African conservation issues. 相似文献