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《Bioorganic & medicinal chemistry》2020,28(11):115492
Effective chemotherapy for solid cancers is challenging due to a limitation in permeation that prevents anticancer drugs from reaching the center of the tumor, therefore unable to limit cancer cell growth. To circumvent this issue, we planned to apply the drugs directly at the center by first collapsing the outer structure. For this, we focused on cell–cell communication (CCC) between N-glycans and proteins at the tumor cell surface. Mature N-glycans establish CCC; however, CCC is hindered when numerous immature N-glycans are present at the cell surface. Inhibition of Golgi mannosidases (GMs) results in the transport of immature N-glycans to the cell surface. This can be employed to disrupt CCC. Here, we describe the molecular design and synthesis of an improved GM inhibitor with a non-sugar mimic scaffold that was screened from a compound library. The synthesized compounds were tested for enzyme inhibition ability and inhibition of spheroid formation using cell-based methods. Most of the compounds designed and synthesized exhibited GM inhibition at the cellular level. Of those, AR524 had higher inhibitory activity than a known GM inhibitor, kifunensine. Moreover, AR524 inhibited spheroid formation of human malignant cells at low concentration (10 µM), based on the disruption of CCC by GM inhibition. 相似文献
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A second Warburg-like effect in cancer metabolism: The metabolic shift of glutamine-derived nitrogen
Manabu Kodama Keiichi I. Nakayama 《BioEssays : news and reviews in molecular, cellular and developmental biology》2020,42(12):2000169
Carbon and nitrogen are essential elements for life. Glucose as a carbon source and glutamine as a nitrogen source are important nutrients for cell proliferation. About 100 years ago, it was discovered that cancer cells that have acquired unlimited proliferative capacity and undergone malignant evolution in their host manifest a cancer-specific remodeling of glucose metabolism (the Warburg effect). Only recently, however, was it shown that the metabolism of glutamine-derived nitrogen is substantially shifted from glutaminolysis to nucleotide biosynthesis during malignant progression of cancer—which might be referred to as a “second” Warburg effect. In this review, address the mechanism and relevance of this metabolic shift of glutamine-derived nitrogen in human cancer. We also examine the clinical potential of anticancer therapies that modulate the metabolic pathways of glutamine-derived nitrogen. This shift may be as important as the shift in carbon metabolism, which has long been known as the Warburg effect. 相似文献
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《Chirality》2017,29(5):213-220
Optically pure, diastereomeric aziridine amides built on the chiral skeletons of camphor, fenchone, and menthone have proven to be highly efficient ligands for enantioselective asymmetric direct aldol reaction in the presence of water and zinc triflate. Desired products were formed in moderate to high chemical yields (up to 95%) and with enantiomeric excess up to 99%. The influence of the stereogenic centers located at the aziridine subunit on the stereochemical course of the reaction is discussed. 相似文献
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《Current biology : CB》2020,30(12):2260-2274.e6
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Christian P Craddock Nicolette Adams Fiona M Bryant Smita Kurup Peter J Eastmond 《Plant signaling & behavior》2015,10(10)
Coordination of membrane lipid biosynthesis is important for cell function during plant growth and development. Here we summarize our recent work on PHOSPHATIDIC ACID PHOSPHOHYDROLASE (PAH) which suggests that this enzyme is a key regulator of phosphaticylcholine (PC) biosynthesis in Arabidopsis thaliana. Disruption of PAH activity elevates phosphatidic acid (PA) levels and stimulates PC biosynthesis and biogenesis of the endoplasmic reticulum (ER). Furthermore, the activity of PHOSPHOCHOLINE CYTIDYLYLTRANSFERASE (CCT), which is the key enzyme controlling the rate of PC biosynthesis, is directly stimulated by PA and expression of a constitutively active version of CCT replicates the effects of PAH disruption. Hence PAH activity can control the abundance of PA, which in turn can modulate CCT activity to govern the rate of PC biosynthesis. Crucially it is not yet clear how PAH activity is regulated in Arabidopsis but there is evidence that PAH1 and PAH2 are both phosphorylated and further work will be required to investigate whether this is functionally significant. 相似文献
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Received 20 September 2001/ Accepted in revised form 10 October 2001 相似文献
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Phenylalanine-U-14C and isoliquiritigenin-9-14C were readily incorporated into the antifungal pterocarpan hydroxyphaseollin in soybean hypocotyls that were inoculated with incompatible strains of the phytopathogenic fungus Phytophthora megasperma var. sojae. Hydroxyphaseollin accounted for over half of the phenylalanine and isoliquiritigenin incorporated into ethyl acetate soluble compounds. Daidzein, coumestrol, and sojagol were identified as major compounds which accumulated coordinately with hydroxyphaseollin and contained significant amounts of radioactivity from the labelled isoflavanoid precursors. Hydroxyphaseollin was not present in healthy soybean plants and was not detected until ca. 16 hr after inoculation with the fungus. The pterocarpan then accumulated rapidly between 16 and 48 hr after inoculation, while the greatest accumulations of daidzein, coumestrol, and sojagol occurred between 48 and 72 hr after inoculation, when hydroxyphaseollin accumulation had ceased. Although soybean hypocotyls contained the anthocyanin malvin, neither this compound nor any other flavone pathway product was observed to accumulate after fungus-inoculation. The results therefore indicate that the accumulation of hydroxyphaseollin in fungus-inoculated soybean hypocotyls involves the activation of isoflavanoid biosynthesis with 'direction' of metabolic intermediates to biosynthesis of the pterocarpan. 相似文献