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排序方式: 共有942条查询结果,搜索用时 15 毫秒
91.
Jin M Kleinberg A Cooke A Gokhale PC Foreman K Dong H Siu KW Bittner MA Mulvihill KM Yao Y Landfair D O'Connor M Mak G Pachter JA Wild R Rosenfeld-Franklin M Ji Q Mulvihill MJ 《Bioorganic & medicinal chemistry letters》2011,21(4):1176-1180
Preclinical and emerging clinical evidence suggests that inhibiting insulin-like growth factor 1 receptor (IGF-1R) signaling may offer a promising therapeutic strategy for the treatment of several types of cancer. This Letter describes the medicinal chemistry effort towards a series of 8-amino-imidazo[1,5-a]pyrazine derived inhibitors of IGF-1R which features a substituted quinoline moiety at the C1 position and a cyclohexyl linking moiety at the C3 position. Lead optimization efforts which included the optimization of structure-activity relationships and drug metabolism and pharmacokinetic properties led to the identification of compound 9m, a potent, selective and orally bioavailable inhibitor of IGF-1R with in vivo efficacy in an IGF-driven mouse xenograft model. 相似文献
92.
In this study, we have rewired cell surfaces with ketone and oxyamine molecules based on liposome fusion for applications in cell-surface engineering. Lipid vesicles, functionalized with ketone and oxyamine molecules, display complementary chemistry and undergo recognition, docking, and subsequent fusion upon covalent oxime bond formation. Liposome fusion was characterized by several techniques including matrix-assisted laser-desorption/ionization mass spectrometry (MALDI-MS), light scattering, fluorescence resonance energy transfer (FRET), and transmission electron microscopy (TEM). When cultured with cells, ketone- and oxyamine-containing liposomes undergo spontaneous membrane fusion to present the respective molecules from cell surfaces. Ketone-functionalized cell surfaces serve as sites for chemoselective ligation with oxyamine-conjugated molecules. We tailored and fluorescently labeled cell surfaces with an oxyamine-conjugated rhodamine dye. As an application of this cell-surface engineering strategy, ketone- and oxyamine-functionalized cells were patterned on oxyamine- and ketone-presenting surfaces, respectively. Cells adhered, spread, and proliferated in the patterned regions via interfacial oxime linkage. The number of ketone molecules on the cell surface was also quantified by flow cytometry. 相似文献
93.
94.
This study aimed to express two major drug-metabolizing human hepatic cytochromes P450 (CYPs), CYP2D6 and CYP3A4, together
with NADPH-cytochrome P450 oxidoreductase (OxR) in Escherichia coli and to evaluate their catalytic activities. Full length cDNA clones of both isoforms in which the N-terminus was modified
to incorporate bovine CYP17α sequence were inserted into a pCWori+ vector. The modified CYP cDNAs were subsequently expressed individually, each together with OxR by means of separate, compatible
plasmids with different antibiotic selection markers. The expressed proteins were evaluated by immunoblotting and reduced
CO difference spectral scanning. Enzyme activities were examined using high performance liquid chromatography (HPLC) assays
with probe substrates dextromethorphan and testosterone for CYP2D6 and CYP3A4, respectively. Results from immunoblotting demonstrated
the presence of both CYP proteins in bacterial membranes and reduced CO difference spectra of the cell preparations exhibited
the characteristic absorbance peak at 450 nm. Co-expressed OxR also demonstrated an activity level comparable to literature
values. Kinetic parameters, Km and Vmax values determined from the HPLC assays also agreed well with literature values. As a conclusion, the procedures described
in this study provide a relatively convenient and reliable means of producing catalytically active CYP isoforms suitable for
drug metabolism and interaction studies. 相似文献
95.
Carter BZ Mak DH Morris SJ Borthakur G Estey E Byrd AL Konopleva M Kantarjian H Andreeff M 《Apoptosis : an international journal on programmed cell death》2011,16(1):67-74
XIAP, a potent caspase inhibitor, is highly expressed in acute myeloid leukemia (AML) cells and contributes to chemoresistance.
A multi-center phase 1/2 trial of XIAP antisense oligonucleotide AEG35156 in combination with idarubicin/cytarabine was conducted
in 56 patients with relapsed/refractory AML. Herein we report the pharmacodynamic studies of the patients enrolled at M. D.
Anderson Cancer Center. A total of 13 patients were enrolled in our institution: five in phase 1 (12–350 mg/m2 AEG35156) and eight in phase 2 (350 mg/m2 AEG35156) of the protocol. AEG35156 was administered on 3 consecutive days and then weekly up to a maximum of 35 days. Blood
samples were collected from patients on days 1 through 5 and on day 28–35 post-chemotherapy for detection of XIAP levels and
apoptosis. AEG35156 treatment led to dose-dependent decreases of XIAP mRNA levels (42–100% reduction in phase 2 patients).
XIAP protein levels were reduced in all five samples measured. Apoptosis induction was detected in 1/4 phase 1 and 4/5 phase
2 patients. Importantly, apoptosis was most pronounced in CD34
+
38
−
AML stem cells and all phase 2 patients showing apoptosis induction in CD34
+
38
−
cells achieved response. We conclude that at 350 mg/m2, AEG35156 is effective in knocking down XIAP in circulating blasts accompanied by the preferential induction of apoptosis
in CD34
+
38
−
AML stem cells. 相似文献
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98.
Vivet-Boudou V Isel C Sleiman M Smyth R Ben Gaied N Barhoum P Laumond G Bec G Götte M Mak J Aubertin AM Burger A Marquet R 《PloS one》2011,6(11):e27456
The occurrence of resistant viruses to any of the anti-HIV-1 compounds used in the current therapies against AIDS underlies the urge for the development of new drug targets and/or new drugs acting through novel mechanisms. While all anti-HIV-1 nucleoside analogues in clinical use and in clinical trials rely on ribose modifications for activity, we designed nucleosides with a natural deoxyribose moiety and modifications of position 8 of the adenine base. Such modifications might induce a steric clash with helix αH in the thumb domain of the p66 subunit of HIV-1 RT at a distance from the catalytic site, causing delayed chain termination. Eleven new 2'-deoxyadenosine analogues modified on position 8 of the purine base were synthesized and tested in vitro and in cell-based assays. In this paper we demonstrate for the first time that chemical modifications on position 8 of 2'-deoxyadenosine induce delayed chain termination in vitro, and also inhibit DNA synthesis when incorporated in a DNA template strand. Furthermore, one of them had moderate anti-HIV-1 activity in cell-culture. Our results constitute a proof of concept indicating that modification on the base moiety of nucleosides can induce delayed polymerization arrest and inhibit HIV-1 replication. 相似文献
99.