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Claudia Karnthaler‐Benbakka Bettina Koblmüller Marlene Mathuber Katharina Holste Walter Berger Petra Heffeter Christian R. Kowol Bernhard K. Keppler 《化学与生物多样性》2019,16(1)
Since several decades, the prodrug concept has raised considerable interest in cancer research due to its potential to overcome common problems associated with chemotherapy. However, for small‐molecule tyrosine kinase inhibitors, which also cause severe side effects, hardly any strategies to generate prodrugs for therapeutic improvement have been reported so far. Here, we present the synthesis and biological investigation of a cathepsin B‐cleavable prodrug of the VEGFR inhibitor sunitinib. Cell viability assays and Western blot analyses revealed, that, in contrast to the non‐cathepsin B‐cleavable reference compound, the prodrug shows activity comparable to the original drug sunitinib in the highly cathepsin B‐expressing cell lines Caki‐1 and RU‐MH. Moreover, a cathepsin B cleavage assay confirmed the desired enzymatic activation of the prodrug. Together, the obtained data show that the concept of cathepsin B‐cleavable prodrugs can be transferred to the class of targeted therapeutics, allowing the development of optimized tyrosine kinase inhibitors for the treatment of cancer. 相似文献
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Martijn F Schenk Jan HG Cordewener Antoine HP America Wendy PC van't Westende Marinus JM Smulders Luud JWJ Gilissen 《BMC plant biology》2009,9(1):24
Background
Bet v 1 is an important cause of hay fever in northern Europe. Bet v 1 isoforms from the European white birch (Betula pendula) have been investigated extensively, but the allergenic potency of other birch species is unknown. The presence of Bet v 1 and closely related PR-10 genes in the genome was established by amplification and sequencing of alleles from eight birch species that represent the four subgenera within the genus Betula. Q-TOF LC-MSE was applied to identify which PR-10/Bet v 1 genes are actually expressed in pollen and to determine the relative abundances of individual isoforms in the pollen proteome. 相似文献4.
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This is an overview of the mutant strain Clostridium beijerinckii BA101 which produces solvents (acetone–butanol–ethanol, ABE) at elevated levels. This organism expresses high levels of amylases
when grown on starch. C. beijerinckii BA101 hydrolyzes starch effectively and produces solvent in the concentration range of 27–29 g l−1. C. beijerinckii BA101 has been characterized for both substrate and butanol inhibition. Supplementing the fermentation medium (MP2) with
sodium acetate enhances solvent production to 33 g l−1. The results of studies utilizing commercial fermentation medium and pilot plant-scale reactors are consistent with the results
using small-scale reactors. Pervaporation, a technique to recover solvents, has been applied to fed-batch reactors containing
C. beijerinckii BA101, and solvent production as high as 165 g l−1 has been achieved. Immobilization of C. beijerinckii BA101 by adsorption and use in a continuous reactor resulted in reactor productivity of 15.8 g l−1 h−1. Recent economic studies employing C. beijerinckii BA101 suggested that butanol can be produced at US$0.20–0.25 lb−1 by employing batch fermentation and distillative recovery. Application of new technologies such as pervaporation, fed-batch
culture, and immobilized cell reactors is expected to further reduce these prices.
Journal of Industrial Microbiology & Biotechnology (2001) 27, 287–291.
Received 12 September 2000/ Accepted in revised form 27 January 2001 相似文献
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S Cohen HP LIN 《Journal of neurochemistry》1972,19(2):513-523
Abstract— The diethyl ester of α-fluoroglutarate (DEFG), an inhibitor of glutamate dehydrogenase, was prepared, and its effect on glutamate and phosphates in slices of rabbit cerebral cortex was examined. The primary effect of the drug on cortical slices incubating in a Krebs-Ringer glucose medium was to decrease the tissue levels of glutamate in association with decreased levels and turnover of high-energy phosphates. Assimilation of exogenous glutamate by the slices was partially blocked in the presence of the drug and severely depressed oxidative phosphorylation resulted when glutamate and DEFG were both present in the incubation mixture. The results suggested a significant relationship between the activity of cerebral glutamate dehydrogenase and oxidative phosphorylation. During incubation in a Krebs-Ringer glucose medium the endogenous pool of free amino acids in the cortical slice partitioned with the medium. Little or no glutamate, aspartate or GABA was present in the medium after incubation, but glycine, alanine, threonine, serine and glutamine did partition to varying degrees, with over one-half of the glutamine present in the incubation medium. With the exception of ‘leakage’ of aspartate, the partitioning patterns were relatively unaffected by the presence of added glutamate or DEFG. 相似文献
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An overview of the serpin superfamily 总被引:2,自引:1,他引:1
Law RH Zhang Q McGowan S Buckle AM Silverman GA Wong W Rosado CJ Langendorf CG Pike RN Bird PI Whisstock JC 《Genome biology》2006,7(5):216-11
Serpins are a broadly distributed family of protease inhibitors that use a conformational change to inhibit target enzymes. They are central in controlling many important proteolytic cascades, including the mammalian coagulation pathways. Serpins are conformationally labile and many of the disease-linked mutations of serpins result in misfolding or in pathogenic, inactive polymers. 相似文献
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Kozina V Geist D Kubinová L Bilić E Karnthaler HP Waitz T Janáček J Chernyavskiy O Krhen I Ježek D 《Histochemistry and cell biology》2011,135(2):215-228
Within the human testis, Reinke’s crystals are found in Leydig cells but their nature and function are poorly understood.
The aim of our study was to investigate the properties of Reinke’s crystals in man with the normal morphology of the testis
(control group) and infertile patients diagnosed with cryptorchidism. 20 biopsies from infertile patients and six biopsies
from men with regular spermatogenesis (20–30 years.) were used. Sections of the testis tissue were stained with haematoxylin
and eosin and a modified Masson’s method. Specimens were observed by bright field, confocal and transmission electron microscopy
(TEM). The number of Reinke’s crystals in investigated groups was determined applying stereological methods. In both groups,
Reinke’s crystals were noted within the cytoplasm and nuclei of Leydig cells. Some “free” crystals were found within the interstitial
space, outside Leydig cells. Confocal microscopy proved to be very useful in the assessment of the shape and 3D reconstruction
of the crystal. TEM analysis confirmed a hexagonal form of the crystal, while crystallographic data on sections of 70–300 nm
thickness provided a better insight into the organization of the crystal lattice. Stereological analysis revealed a significant
increase in the number of crystals in cryptorchid testes when compared with controls. Increased number of crystals in cryptorchid
specimens leads to the assumption that the prolonged exposure to higher (abdominal) temperature might stimulate enzymes involved
in the synthesis of the proteins of the crystal. However, the exact molecular nature of the crystal lattice remains in both
normal and cryptorchid testis obscure. 相似文献