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71.
J.N. Lisgarten B.S. Potter J. Aymami H. Oketch-Rabah R.A. Palmer 《Journal of chemical crystallography》2003,33(2):149-153
The crystal and molecular structure of the antimalarial compound 5,7-methoxy-8-(3-methyl-1-buten-3-ol)-coumarin, C16H18O5, M
r = 290.3 Da, has been determined from X-ray diffraction data. The material crystallizes in the monoclinic space group P21/c with 4 molecules per unit cell of dimensions a = 8.9044(9), b = 17.623(1), c = 10.175(1) Å, = 113.97(1)°, crystal density D
c = 1.322 g/cm3. The structure was determined using direct methods and refined by full-matrix least squares to a conventional R index of 0.066 for 2416 measured reflections and 206 parameters.The coumarin ring system is almost planar with the methoxy C atoms rotated slightly out of the coumarin mean plane. Apart from the terminal CH3 groups C(12) and C(13), which are 1.184(3) Å above and –1.315(3) Å below the plane, the 3-methyl-1-buten-3-ol substituent is planar (rms deviation 0.009 Å) making an angle of 6.31(7)° with the phenyl ring. One intermolecular hydrogen bond is present in the crystal structure between O(5)–HO(5) and the symmetry related O(2) oxygen, generated by the symmetry operation (x, 1/2 – y, –1/2 + z). 相似文献
72.
An optimized synthetic route to 7-deaza-8-bromo-cyclic adenosine 5'-diphosphate ribose (7-deaza-8-bromo-cADPR 3), an established cell-permeant, hydrolysis-resistant cyclic adenosine 5'-diphosphate ribose (cADPR) antagonist, is presented. Using NMR analysis, we found that 3 adopted a C-2' endo conformation in the N9-linked ribose and a syn conformation about the N9-glycosyl linkage, which are similar to that of cADPR. The synthetic route was also employed to produce 7-deaza-2'-deoxy-cADPR 4, a potential cell-permeant cADPR analogue. 3 and 4 were more stable to chemical hydrolysis, consistent with the observation that 7-deaza-cADPR analogues are more stable than their parent adenosine derivatives. 3 was also found to be stable to enzyme-mediated hydrolysis using CD38 ectoenzyme. 相似文献
73.
Sureshan KM Trusselle M Tovey SC Taylor CW Potter BV 《The Journal of organic chemistry》2008,73(5):1682-1692
Adenophostin A (AdA) is a potent agonist of the d-myo-inositol 1,4,5-trisphosphate receptor (Ins(1,4,5)P3R). Various 2-aminopurine analogues of AdA were synthesized, all of which (guanophostin 5, 2,6-diaminopurinophostin 6, 2-aminopurinophostin 7, and chlorophostin 8) are more potent than 2-methoxy-N6-methyl AdA, the only benchmark of this class. The 2-amino-6-chloropurine nucleoside 11, from Vorbrüggen condensation of 2-amino-6-chloropurine with appropriately protected disaccharide, served as the advanced common precursor for all the analogues. Alcoholysis provided the precursor for 5, ammonolysis at high temperature the precursor for 6, and ammonolysis under mild conditions the precursor for synthesis of 7 and 8. For 8, the debenzylation of precursor leaving the chlorine untouched was achieved by judicious use of BCl3. The reduced potency of chlorophostin 8 and higher potency of guanophostin 5 in assays of Ca2+ release via recombinant Ins(1,4,5)P3R are in agreement with our model suggesting a cation-pi interaction between AdA and Ins(1,4,5)P3R. The similar potencies of 2,6-diaminopurinophostin (6) and 2-aminopurinophostin (7) concur with previous reports that the 6-NH2 moiety contributes negligibly to the potency of AdA. Molecular modeling of the 2-amino derivatives suggests an interaction between the carboxylate side chain of Glu505 of the receptor and the 2-NH2 of the ligand, but for 2-methoxy-N6-methyl AdA the carboxylate group of Glu505 is deflected away from the methoxy group. A helix-dipole interaction between the 1-phosphate of Ins(1,4,5)P3 and the 2'-phosphate of AdA with alpha-helix 6 of Ins(1,4,5)P3R is postulated. The results support a proposed model for high-affinity binding of AdA to Ins(1,4,5)P3R. 相似文献
74.
Prasuhn DE Kuzelka J Strable E Udit AK Cho SH Lander GC Quispe JD Diers JR Bocian DF Potter C Carragher B Finn MG 《Chemistry & biology》2008,15(5):513-519
The addition of a hexahistidine tag to the N terminus of the hepatitis B capsid protein gives rise to a self-assembled particle with 80 sites of high local density of histidine side chains. Iron protoporphyrin IX has been found to bind tightly at each of these sites, making a polyvalent system of well-defined spacing between metalloporphyrin complexes. The spectroscopic and redox properties of the resulting particle are consistent with the presence of 80 site-isolated bis(histidine)-bound heme centers, comprising a polyvalent b-type cytochrome mimic. 相似文献
75.
James S. Parascandolo Dr. Judith Havemann Helen K. Potter Dr. Fanglu Huang Dr. Elena Riva Jack Connolly Dr. Ina Wilkening Dr. Lijiang Song Prof. Peter F. Leadlay Dr. Manuela Tosin 《Angewandte Chemie (International ed. in English)》2016,55(10):3463-3467
Chemical probes capable of reacting with KS (ketosynthase)‐bound biosynthetic intermediates were utilized for the investigation of the model type I iterative polyketide synthase 6‐methylsalicylic acid synthase (6‐MSAS) in vivo and in vitro. From the fermentation of fungal and bacterial 6‐MSAS hosts in the presence of chain termination probes, a full range of biosynthetic intermediates was isolated and characterized for the first time. Meanwhile, in vitro studies of recombinant 6‐MSA synthases with both nonhydrolyzable and hydrolyzable substrate mimics have provided additional insights into substrate recognition, providing the basis for further exploration of the enzyme catalytic activities. 相似文献
76.
Jackson T Woo LW Trusselle MN Chander SK Purohit A Reed MJ Potter BV 《Organic & biomolecular chemistry》2007,5(20):2940-2952
The synthesis and biological evaluation of a series of novel Dual Aromatase-Sulfatase Inhibitors (DASIs) are described. It is postulated that dual inhibition of the aromatase and steroid sulfatase enzymes, both responsible for the biosynthesis of oestrogens, will be beneficial in the treatment of hormone-dependent breast cancer. The compounds are based upon the Anastrozole aromatase inhibitor template which, while maintaining the haem ligating triazole moiety crucial for enzyme inhibition, was modified to include a phenol sulfamate ester motif, the pharmacophore for potent irreversible steroid sulfatase inhibition. Adaption of a synthetic route to Anastrozole was accomplished via selective radical bromination and substitution reactions to furnish a series of aromatase inhibitory pharmacophores. Linking these fragments to the phenol sulfamate ester moiety employed SN2, Heck and Mitsunobu reactions with phenolic precursors, from where the completed DASIs were achieved via sulfamoylation. In vitro, the lead compound, 11, had a high degree of potency against aromatase (IC50 3.5 nM), comparable with that of Anastrozole (IC50 1.5 nM) whereas, only moderate activity against steroid sulfatase was found. However, in vivo, 11 surprisingly exhibited potent dual inhibition.Compound 11 was modelled into the active site of a homology model of human aromatase and the X-ray crystal structure of steroid sulfatase. 相似文献
77.
Jackson T Woo LW Trusselle MN Chander SK Purohit A Reed MJ Potter BV 《Organic & biomolecular chemistry》2007,5(18):2940-2952
The synthesis and biological evaluation of a series of novel Dual Aromatase-Sulfatase Inhibitors (DASIs) are described. It is postulated that dual inhibition of the aromatase and steroid sulfatase enzymes, both responsible for the biosynthesis of oestrogens, will be beneficial in the treatment of hormone-dependent breast cancer. The compounds are based upon the Anastrozole aromatase inhibitor template which, while maintaining the haem ligating triazole moiety crucial for enzyme inhibition, was modified to include a phenol sulfamate ester motif, the pharmacophore for potent irreversible steroid sulfatase inhibition. Adaption of a synthetic route to Anastrozole was accomplished via selective radical bromination and substitution reactions to furnish a series of inhibitory aromatase pharmacophores. Linking these fragments to the phenol sulfamate ester moiety employed S(N)2, Heck and Mitsunobu reactions with phenolic precursors, from where the completed DASIs were achieved via sulfamoylation. In vitro, the lead compound, 11, had a high degree of potency against aromatase (IC(50) 3.5 nM), comparable with that of Anastrozole (IC(50) 1.5 nM) whereas, only moderate activity against steroid sulfatase was found. However, in vivo, 11 surprisingly exhibited potent dual inhibition. Compound 11 was modelled into the active site of a homology model of human aromatase and the X-ray crystal structure of steroid sulfatase. 相似文献
78.
Dang Q Kasibhatla SR Reddy KR Jiang T Reddy MR Potter SC Fujitaki JM van Poelje PD Huang J Lipscomb WN Erion MD 《Journal of the American Chemical Society》2007,129(50):15491-15502
Excessive glucose production by the liver coupled with decreased glucose uptake and metabolism by muscle, fat, and liver results in chronically elevated blood glucose levels in patients with type 2 diabetes. Efforts to treat diabetes by reducing glucose production have largely focused on the gluconeogenesis pathway and rate-limiting enzymes within this pathway such as fructose-1,6-bisphosphatase (FBPase). The first potent FBPase inhibitors were identified using a structure-guided drug design strategy (Erion, M. D.; et al. J. Am. Chem. Soc. 2007, 129, 15480-15490) but proved difficult to deliver orally. Herein, we report the synthesis and characterization of a series of orally bioavailable FBPase inhibitors identified following the combined discoveries of a low molecular weight inhibitor series with increased potency and a phosphonate prodrug class suitable for their oral delivery. The lead inhibitor, 10A, was designed with the aid of X-ray crystallography and molecular modeling to bind to the allosteric AMP binding site of FBPase. High potency (IC50 = 16 nM) and FBPase specificity were achieved by linking a 2-aminothiazole with a phosphonic acid. Free-energy perturbation calculations provided insight into the factors that contributed to the high binding affinity. 10A and standard phosphonate prodrugs of 10A exhibited poor oral bioavailability (0.2-11%). Improved oral bioavailability (22-47%) was achieved using phosphonate diamides that convert to the corresponding phosphonic acid by sequential action of an esterase and a phosphoramidase. Oral administration of the lead prodrug, MB06322 (30, CS-917), to Zucker Diabetic Fatty rats led to dose-dependent inhibition of gluconeogenesis and endogenous glucose production and consequently to significant blood glucose reduction. 相似文献
79.
A parametric model for synthetic aperture radar measurements 总被引:17,自引:0,他引:17
Gerry M.J. Potter L.C. Gupta I.J. Van Der Merwe A. 《Antennas and Propagation, IEEE Transactions on》1999,47(7):1179-1188
80.
Cobb JM Mattice JD Senseman SA Dumas JA Mersie W Riley MB Potter TL Mueller TC Watson EB 《Journal of AOAC International》2006,89(4):903-912
An interlaboratory study was conducted at 8 locations to assess the stability of pesticides on solid-phase extraction (SPE) disks after incubation at various temperatures and for various time intervals. Deionized water fortified with selected pesticides was extracted by using 2 types of SPE filtration disks (Empore C18 and Speedisk C18XF), and after extraction, the disks were incubated at 3 temperatures (25, 40, and 55 degrees C) and for 2 time intervals (4 and 14 days). Deionized water was fortified with atrazine, carbofuran, and chlorpyrifos by all participating laboratories. In addition, some of the laboratories included 2 of the following pesticides: metolachlor, metribuzin, simazine, chlorothalonil, and malathion. Concurrently, fortified water samples were extracted with the incubated samples by using each disk type at 4 and 14 days. Pesticides had equivalent or greater stability on > or = 1 of the C18 disk types, compared with storage in water. The lowest recoveries of carbofuran (6%) and chlorpyrifos (7%) were obtained at 55 degrees C after storage for 14 days in incubated water. At 55 degrees C after 14 days, the lowest recovery for atrazine was 65% obtained by using Empore disks. Pesticide-specific losses occurred on the C18 disks in this study, underlining the importance of temperature and time interval when water is extracted at remote field locations and the SPE disks containing the extracted pesticides are transported or shipped to a laboratory for elution and analysis. 相似文献