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排序方式: 共有5956条查询结果,搜索用时 62 毫秒
981.
DV Patel RJ Schmidt SA Biller EM Gordon SS Robinson V Manne 《Canadian Metallurgical Quarterly》1995,38(15):2906-2921
The rational design, synthesis, and biological activity of farnesyl diphosphate (FPP)-based inhibitors of the enzyme Ras farnesyl protein transferase (FPT) is described. Compound 3, wherein a beta-carboxylic phosphonic acid type pyrophosphate (PP) surrogate is connected to the hydrophobic farnesyl group by an amide linker, was found to be a potent (I50(FPT) = 75 nM) and selective inhibitor of FPT, as evidenced by its inferior activity against squalene synthetase (I50(SS) = 516 microM) and mevalonate kinase (I50(MK) = > 200 microM). A systematic structure-activity relationship study involving modifications of the farnesyl group, the amide linker, and the PP surrogate of 3 was undertaken. Both the carboxylic and phosphonic acid groups of the beta-carboxylic phosphonic acid PP surrogate are essential for activity, since deletion of either group results in 50-2600-fold loss in activity (6-9, I50 = 4.6-220 microM). The farnesyl group also displays very stringent requirements and does not tolerate one carbon homologation (12, I50 = 17.7 microM), substitution by a dodecyl fragment (14, I50 = 9 microM), or introduction of an extra methyl group at the allylic position (18, I50 = 55 microM). Modifications around the amide linker group of 3 were more forgiving, as evidenced by the activity of N-methyl analog (21, I50 = 0.53 microM), the one carbon atom shorter farnesoic acid-derived retroamide analog (32, I50 = 250 nM), and the exact retroamide analog (49, I50 = 50 nM). FPP analogs such as 3, 32, and 49 are novel, potent, selective, small-sized, nonpeptidic inhibitors of FPT that may find utility as antitumor agents. 相似文献
982.
983.
984.
DV Cumming RJ Heads RS Coffin DM Yellon DS Latchman 《Canadian Metallurgical Quarterly》1996,91(5):367-373
Pre-treatment with the immunosuppressant FK506 is shown to protect primary cardiocytes against a subsequent severe thermal or ischaemic stress. This effect is not observed with the related compounds cyclosporin A or rapamycin. It does not involve induction of the FK506 binding, heat inducible protein hsp56 or of the other heat shock proteins. In addition over-expression of hsp56 does not protect cardiac cells from severe stress in contrast to our previous results with hsp70 and hsp90. These results suggest the FK506 is acting via a novel mechanism to protect cardiac cells against cellular ischaemia which may not be related to its immunosuppressant action. 相似文献
985.
Cardiac herniation through an acquired pericardial defect is potentially fatal. Typically, symptoms manifest within days of a surgical procedure. We describe a patient with late ventricular herniation after surgical formation of an apical pericardial window. 相似文献
986.
EM Franken S Neerken RJ Louwe J Amesz TJ Aartsma 《Canadian Metallurgical Quarterly》1998,37(15):5046-5051
A permanent hole burning study on the Fenna-Matthews-Olson, or FMO, antenna complex of the green sulfur bacterium Prosthecochloris aestuarii was carried out at 6 K. Excitation resulted not only in relatively sharp features resonant with the burn wavelength but also in broad absorbance changes in the wavelength region of 800-820 nm. The shape of the latter changes was almost independent of the wavelength of excitation. Evidence is given that they are induced by a different mechanism than that which causes the resonant holes and that they may be due to a conformational change of the protein. The original spectrum was restored upon warming to 60 K. The effective dephasing times T2, as obtained from the homogeneous line widths, increased from about 0.5 ps at 803 nm to >/=20 ps at 830 nm and are in good agreement with recent measurements of accumulated photon-echo and time-resolved absorbance changes. 相似文献
987.
E Abbate A Albianelli A Azzaroli M Benvenuti B Tesfamariam P Bruni N Cipriani RJ Clarke G Ficcarelli R Macchiarelli G Napoleone M Papini L Rook M Sagri TM Tecle D Torre I Villa 《Canadian Metallurgical Quarterly》1998,393(6684):458-460
One of the most contentious topics in the study of human evolution is that of the time, place and mode of origin of Homo sapiens. The discovery in the Northern Danakil (Afar) Depression, Eritrea, of a well-preserved Homo cranium with a mixture of characters typical of H. erectus and H. sapiens contributes significantly to this debate. The cranium was found in a succession of fluvio-deltaic and lacustrine deposits and is associated with a rich mammalian fauna of early to early-middle Pleistocene age. A magnetostratigraphic survey indicates two reversed and two normal magnetozones. The layer in which the cranium was found is near the top of the lower normal magnetozone, which is identified as the Jaramillo subchron. Consequently, the human remains can be dated at approximately 1 million years before present. 相似文献
988.
989.
Solid-state deuterium and carbon-13 nuclear magnetic resonance (NMR) spectra have been used to study the molecular dynamics and conformation of dipalmitoylphosphatidylethanolamine (DPPE) in both the gel (L beta) and liquid-crystalline (L alpha) phases. For this purpose DPPE was labeled with 13C in the carbonyl group of the sn-2 chain and with 2H at three different positions--4, 8, and 12--of the sn-2 chain, at the 2 position of the glycerol backbone, and at the 1 position of the ethanolamine head group. The 13C carbonyl and 2H chain spectra indicate that in the gel phase the DPPE molecules are diffusing about their long axes at rates of 10(5)-10(6) s-1 and the acyl chains are in an approximately all-trans conformation. The glycerol backbone spectra suggest that the backbone is in a gauche conformation in the gel state, rather than a trans conformation such as found in single crystals. The head group spectra in the gel phase are broad, featureless lines of about 20-kHz width. At the L beta leads to L alpha phase transition several changes take place. As is well-known, the chains disorder, and fast long-axis rotational diffusion begins, which results in the sharp, axially symmetric L alpha phase 2H spectra, which are a factor of 2 narrower than those observed in the L beta phase. The head group spectra also sharpen substantially at the transition, although their total width remains approximately constant. The invariance of the spectral width suggests that the average head group conformation is similar in both phases. However, the sharper spectra seen in the L alpha phase indicate that the rates of the head group motions in this phase are at least 3 orders of magnitude faster than those in the L beta phase. Thirdly, the 2H spectra of the glycerol backbone labeled DPPE narrow by a factor of about 4, and we believe this is due to a conformational change in this region of the molecule. Consistent with this interpretation is the fact that the powder pattern exhibited by the sn-2 13C = O in the L beta phase collapses to an isotropic-like line at the phase transition. 相似文献
990.
RJ Bulger 《Canadian Metallurgical Quarterly》1981,245(9):955-956