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141.
Kang FA Guan J Jain N Allan G Linton O Tannenbaum P Chen X Xu J Zhu P Gunnet J Demarest K Lundeen S Sui Z 《Bioorganic & medicinal chemistry letters》2007,17(9):2531-2534
Efficient parallel synthesis of novel 7-oxa-steroids 4 has been achieved from the key intermediate 3 via a one-pot four-step sequence. oxa-Steroids 4 with various ortho-, meta-, and para-monosubstituents on the phenyl ring, as well as disubstituted phenyl and heterocycles, were evaluated for progesterone receptor (PR) and glucocorticoid receptor (GR) antagonist activities. SAR study demonstrated that the para-fluorinated substituents on the phenyl ring not only increased the potency for PR in a T47D cell functional assay, but also improved the selectivity over GR in an A549 cell functional assay. The para-fluorophenyl oxa-steroid 4l and the para-trifluoromethylphenyl oxa-steroid 4p were found to be remarkably more potent and more selective PR antagonists than mifepristone, with subnanomolar potency and about 140-fold selectivity over GR. Molecular modeling of the oxa-steroid bound to PR provided meaningful insight for the SAR study. oxa-Steroids 4a and 4b were found to be more efficacious than mifepristone in vivo in a rat uterine complement C3 assay via the oral route, although they were less than or equally potent to mifepristone in the T47D assay. 相似文献
142.
Kang FA Allan G Guan J Jain N Linton O Tannenbaum P Xu J Zhu P Gunnet J Chen X Demarest K Lundeen S Sui Z 《Bioorganic & medicinal chemistry letters》2007,17(4):907-910
A novel series of oxa-steroids 6 derived from (8S, 13S, 14R)-7-oxa-estra-4,9-diene-3,17-dione 1 have been synthesized and identified as potent and selective progesterone receptor antagonists. These novel oxa-steroids showed similar potency to mifepristone. Preliminary SAR study resulted in the most potent 17-phenylethynyl oxa-steroid 6i wih an IC(50) of 1.4nM. In contrast to the equipotent mifepristone toward the progesterone receptor (PR) and glucocorticoid receptor (GR), compound 6i had over 200-fold selectivity for PR over GR. 相似文献
143.
The quality of pharmaceutical products such as ginseng is important for ensuring consumer safety and efficacy. Ginseng is
an expensive herb, and adulteration with other cheaper products may occur. Quality assurance of ginseng is needed since many
of its commercial products now come in various formulations such as capsules, powder, softgels and tea. Thus traditional means
of authentication via smell, taste or physical appearance are hardly reliable. Herbs like ginseng tend to exhibit characteristic
infrared fingerprints due to their different chemical constituents. Here we report for the first time a rapid means of distinguishing
American and Asian ginsengs from two morphological fakes – sawdust and Platycodon grandiflorum, via pattern differences and principal component analysis of their infrared spectra. Our results show that ginseng can be
distinguished from both sawdust and Platycodon grandiflorum, hence there is a potential of using infrared spectroscopy as a novel analytical technique in the authentication of ginseng. 相似文献
144.
Propranolol is a nonselective beta-blocker of the beta-adrenergic receptors, and the S-enantiomer is more active compared with the R-enantiomer. Clinically, it has been shown to be effective in hypermetabolic burn patients by decreasing cardiac work, protein catabolism, and lipolysis. While gene expression profiles have recently been reported in children receiving propranolol treatment, variations from one individual to another may have influenced the data analysis. Using iTRAQ-coupled 2D LC-MS/MS analysis, we report here the first study of protein profile in vascular smooth muscle cells incubated separately with the two enantiomers of propranolol. Four types of cellular proteins including metabolic enzymes, signaling molecules, cytoskeletal proteins, and those involved in DNA synthesis/protein translation displayed changes. The higher protein level of a number of enzymes involved in cellular anabolism and antioxidant activity in cells incubated with the S-enantiomer, as revealed by LC-MS/MS, was further supported by real-time PCR and Western blot analyses. Significantly, the increase in the anabolic activity associated with the higher level of metabolic enzymes was also supported by the higher intracellular concentration of the metabolic cofactor NAD+ which was a result of an increased oxidation of NADH. Our findings therefore provide molecular evidence on metabolic effect associated with propranolol treatment. The metabolic enzymes identified in our study may in turn be useful targets for future pharmaceutical interventions to reduce clinical side effects following propranolol treatment. 相似文献
145.
Chen Shuang Sun Yanyun Li Fei Zhang Xinyu Hu Xiaoyan Zhao Xiaoyun Li Yixuan Li Hui Zhang Jianliang Liu Wenlan Zheng Guo-qing Jin Xinchun 《Cellular and molecular neurobiology》2022,42(7):2407-2422
Cellular and Molecular Neurobiology - The only food and drug administration (FDA)-approved drug currently available for the treatment of acute ischemic stroke is tissue plasminogen activator (tPA),... 相似文献
146.
147.
Leifu Chang Xianwei Liu Yanbing Li Cui-Cui Liu Fan Yang Jindong Zhao Sen-Fang Sui 《Cell research》2015,25(6):726-737
Phycobilisomes (PBSs) are light-harvesting antennae that transfer energy to photosynthetic reaction centers in cyanobacteria and red algae. PBSs are supermolecular complexes composed of phycobiliproteins (PBPs) that bear chromophores for energy absorption and linker proteins. Although the structures of some individual components have been determined using crystallography, the three-dimensional structure of an entire PBS complex, which is critical for understanding the energy transfer mechanism, remains unknown. Here, we report the structures of an intact PBS and a PBS in complex with photosystem II (PSII) from Anabaena sp. strain PCC 7120 using single-particle electron microscopy in combination with biochemical and molecular analyses. In the PBS structure, all PBP trimers and the conserved linker protein domains were unambiguously located, and the global distribution of all chromophores was determined. We provide evidence that ApcE and ApcF are critical for the formation of a protrusion at the bottom of PBS, which plays an important role in mediating PBS interaction with PSII. Our results provide insights into the molecular architecture of an intact PBS at different assembly levels and provide the basis for understanding how the light energy absorbed by PBS is transferred to PSII. 相似文献
148.
149.
Xiaoyun Tang Matthew G. K. Benesch David N. Brindley 《Journal of lipid research》2015,56(11):2048-2060
Lipid phosphate phosphatases (LPPs) are a group of enzymes that belong to a phosphatase/phosphotransferase family. Mammalian LPPs consist of three isoforms: LPP1, LPP2, and LPP3. They share highly conserved catalytic domains and catalyze the dephosphorylation of a variety of lipid phosphates, including phosphatidate, lysophosphatidate (LPA), sphingosine 1-phosphate (S1P), ceramide 1-phosphate, and diacylglycerol pyrophosphate. LPPs are integral membrane proteins, which are localized on plasma membranes with the active site on the outer leaflet. This enables the LPPs to degrade extracellular LPA and S1P, thereby attenuating their effects on the activation of surface receptors. LPP3 also exhibits noncatalytic effects at the cell surface. LPP expression on internal membranes, such as endoplasmic reticulum and Golgi, facilitates the metabolism of internal lipid phosphates, presumably on the luminal surface of these organelles. This action probably explains the signaling effects of the LPPs, which occur downstream of receptor activation. The three isoforms of LPPs show distinct and nonredundant effects in several physiological and pathological processes including embryo development, vascular function, and tumor progression. This review is intended to present an up-to-date understanding of the physiological and pathological consequences of changing the activities of the different LPPs, especially in relation to cell signaling by LPA and S1P. 相似文献