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排序方式: 共有665条查询结果,搜索用时 31 毫秒
101.
Sébastien L. Degorce Rana Anjum Keith S. Dillman Lisa Drew Sam D. Groombridge Christopher T. Halsall Eva M. Lenz Nicola A. Lindsay Michele F. Mayo Jennifer H. Pink Graeme R. Robb James S. Scott Stephen Stokes Yafeng Xue 《Bioorganic & medicinal chemistry》2018,26(4):913-924
We have developed a series of orally efficacious IRAK4 inhibitors, based on a scaffold hopping strategy and using rational structure based design. Efforts to tackle low permeability and high efflux in our previously reported pyrrolopyrimidine series (Scott et al., 2017) led to the identification of pyrrolotriazines which contained one less formal hydrogen bond donor and were intrinsically more lipophilic. Further optimisation of substituents on this pyrrolotriazine core culminated with the discovery of 30 as a promising in vivo probe to assess the potential of IRAK4 inhibition for the treatment of MyD88 mutant DLBCL in combination with a BTK inhibitor. When tested in an ABC-DLBCL model with a dual MyD88/CD79 mutation (OCI-LY10), 30 demonstrated tumour regressions in combination with ibrutinib. 相似文献
102.
Anna V. Glyakina Ilya V. Likhachev Nikolay K. Balabaev Oxana V. Galzitskaya 《Journal of structural biology》2018,201(2):162-170
Spectrins belong to repetitive three-helix bundle proteins that have vital functions in multicellular organisms and are of potential value in nanotechnology. To reveal the unique physical features of repeat proteins we have studied the structural and mechanical properties of three repeats of chicken brain α-spectrin (R15, R16 and R17) at the atomic level under stretching at constant velocities (0.01, 0.05 and 0.1?Å·ps?1) and constant forces (700 and 900?pN) using molecular dynamics (MD) simulations at T?=?300?K. 114 independent MD simulations were performed and their analysis has been done. Despite structural similarity of these domains we have found that R15 is less mechanically stable than R16, which is less stable than R17. This result is in agreement with the thermal unfolding rates. Moreover, we have observed the relationship between mechanical stability, flexibility of the domains and the number of aromatic residues involved in aromatic clusters. 相似文献
103.
A rapid and efficient strategy has been developed for the general synthesis of complex peptide aldehydes. N(alpha)-Benzyloxycarbonylamino acids were converted to protected aldehyde building blocks for solid-phase synthesis in four steps and moderate overall yields. The aldehydes were protected as 1,3-dioxolanes except for one case where a dimethyl acetal was used. These protected amino aldehyde monomers were then incorporated onto 5-[(2 or 4)-formyl-3,5-dimethoxyphenoxy]butyryl-resin (BAL-PEG-PS) by reductive amination, following which the penultimate residue was introduced by HATU-mediated acylation. The resultant resin-bound dipeptide unit, anchored by a backbone amide linkage (BAL), was extended further by routine Fmoc chemistry procedures. Several model peptide aldehydes were prepared in good yields and purities. Some epimerization of the C-terminal residue occurred (10% to 25%), due to the intrinsic stereolability conferred by the aldehyde functional group, rather than any drawbacks to the synthesis procedure. 相似文献
104.
A. Urrestarazu S. Vissers I. Iraqui M. Grenson 《Molecular & general genetics : MGG》1998,257(2):230-237
This paper reports the first isolation of Saccharomyces cerevisiae mutants lacking aromatic aminotransferase I activity (aro8), and of aro8 aro9 double mutants which are auxotrophic for both phenylalanine and tyrosine, because the second mutation, aro9, affects aromatic aminotransferase II. Neither of the single mutants displays any nutritional requirement on minimal ammonia
medium. In vitro, aromatic aminotransferase I is active not only with the aromatic amino acids, but also with methionine,
α-aminoadipate, and leucine when phenylpyruvate is the amino acceptor, and in the reverse reactions with their oxo-acid analogues
and phenylalanine as the amino donor. Its contribution amounts to half of the glutamate:2-oxoadipate activity detected in
cell-free extracts and the enzyme might be identical to one of the two known α-aminoadipate aminotransferases. Aromatic aminotransferase
I has properties of a general aminotransferase which, like several aminotransferases of Escherichia coli, may be able to play a role in several otherwise unrelated metabolic pathways. Aromatic aminotransferase II also has a broader
substrate specificity than initially described. In particular, it is responsible for all the measured kynurenine aminotransferase
activity. Mutants lacking this activity grow very slowly on kynurenine medium.
Received: 21 October 1996 / Accepted: 23 September 1997 相似文献
105.
The gene coding for the 3-dehydroquinate synthetase (aroB) of Neisseria gonorrhoeae has been cloned by functional complementation of an Escherichia coli aroB mutant. The aroB gene isolated from a gonococcal plasmid library encodes a 359 amino acid protein with a molecular mass of 38.6 kDa. Alignment
of different prokaryotic and eukaryotic aroB gene products reveals an overall identity ranging from 33 to 55%. An open reading frame coding for an aroK homologue is located immediately upstream of aroB. Downstream of aroB a region of inverted repeats and a gene showing high homology to yafJ of E. coli has been identified. Disruption of aroB generates a gonococcal mutant that is unable to grow in the absence of aromatic compounds. Complementation of the mutant
with the intact aroB gene intrans indicates that the gene is responsible for the auxotrophic phenotype. In infection assays with AroB-deficient gonococcal
strains, binding, entry and short-term survival in epithelial cells is not affected. The aroB gene might be useful as a selectable marker and target for attenuation of a gonococcal live vaccine strain or as a biosafe
laboratory strain.
Received: 23 September 1997 / Accepted: 19 November 1997 相似文献
106.
When the acetogen Clostridium formicoaceticum was cultivated on mixtures of aromatic compounds (e.g., 4-hydroxybenzaldehyde plus vanillate), the oxidation of aromatic
aldehyde groups occurred more rapidly than did O-demethylation. Likewise, when fructose and 4-hydroxybenzaldehyde were simultaneously
provided as growth substrates, fructose was utilized only after the aromatic aldehyde group was oxidized to the carboxyl level.
Aromatic aldehyde oxidoreductase activity was constitutive (activities approximated 0.8 U mg–1), and when pulses of 4-hydroxybenzaldehyde were added during fructose-dependent growth, the rate at which fructose was utilized
decreased until 4-hydroxybenzaldehyde was consumed. Although 4-hydroxybenzaldehyde inhibited the capacity of cells to metabolize
fructose, lactate or gluconate were consumed simultaneously with 4-hydroxybenzaldehyde, and lactate or aromatic compounds
lacking an aldehyde group were utilized concomitantly with fructose. These results demonstrate that (1) aromatic aldehydes
can be utilized as cosubstrates and have negative effects on the homoacetogenic utilization of fructose by C. formicoaceticum, and (2) the consumption of certain substrates by this acetogen is not subject to catabolite repression by fructose.
Received: 14 May 1998 / Accepted: 7 August 1998 相似文献
107.
Herein we report the synthesis of a new series of aromatic sulfamates investigated for the inhibition of four human (h) isoforms of zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), hCA I, II, IV, and IX. The reported derivatives, obtained by a sulfamoylation reaction of the corresponding phenolic precursors, bear arylthiazolin-4-one moieties as spacers between the benzenesulfamate fragment which binds the zinc ion from the active site, and the tail of the inhibitor. Thiazolin-4-ones are biologically privileged scaffolds, endowed with versatile biological activity, such as an anti-proliferative action. Phenolic precursors, also evaluated for CA inhibition, did not exhibit noteworthy efficacy in inhibiting the screened hCAs, whereas low nanomolar inhibitors were evidenced within the sulfamates subset mainly against hCA II (KIs in the range of 28.7–84.3 nM) and IX (KIs in the range of 17.6–73.3 nM). The variety of substituents appended at the outer aromatic portion almost generally reduced the inhibitory efficacy against isoforms II and IV, increasing instead that against the tumor-associated isoform IX. 相似文献
108.
Chorismate synthase, the seventh enzyme in the shikimate pathway, catalyzes the transformation of 5-enolpyruvylshikimate 3-phosphate
to chorismate which is the last common precursor in the biosynthesis of numerous aromatic compounds in bacteria, fungi and
plants. The enzyme has an absolute requirement for reduced FMN as a cofactor, although the 1,4-anti elimination of phosphate and the C(6proR)-hydrogen does not involve a net redox change. The role of the reduced FMN in catalysis has long been elusive. However, recent
detailed kinetic and bioorganic approaches have fundamentally advanced our understanding of the mechanism of action, suggesting
an initial electron transfer from tightly bound reduced flavin to the substrate, a process which results in C—O bond cleavage.
Studies on chorismate synthases from bacteria, fungi and plants revealed that in these organisms the reduced FMN cofactor
is made available in different ways to chorismate synthase: chorismate synthases in fungi – in contrast to those in bacteria
and plants – carry a second enzymatic activity which enables them to reduce FMN at the expense of NADPH. Yet, as shown by
the analysis of the corresponding genes, all chorismate synthases are derived from a common ancestor. However, several issues
revolving around the origin of reduced FMN, as well as the possible regulation of the enzyme activity by means of the availability
of reduced FMN, remain poorly understood. This review summarizes recent developments in the biochemical and genetic arena
and identifies future aims in this field.
Received: 22 June 1998 / Accepted: 7 August 1998 相似文献
109.
R. K. Bentsen-Farmen 《Biomarkers》1999,4(1):37-47
Induction of cytochrome P450 enzymes by exposure to polycyclic aromatic hydrocarbons (PAH) can result in both decreased or increased PAH adduct levels. The lung is a main target site for PAH-carcinogenesis. By HPLC determination of B[ a]P-r-7, t-8-dihydrodiol, t-9, 10-epoxide (BPDE-I)-DNA adducts in rat, the level of the ultimate carcinogenic B[a]P-metabolite was higher in lungs than in liver. However, measured by immunoassay, the total benzo[a]pyrene (B[a]P)-DNA adduct levels were higher in liver than in lungs. Induction of CYP1A1 in vivo in rat by repeated i.p. doses of methylcholanthrene (MC) prior to a single dose of B[a]P resulted in a 2.4 times increase in CYP1A1 activity in liver tissue and 1.5 times higher levelsof total B[a]P-DNA adducts in lung and liver compared with controls which only received B[a]P. Increased levels of BPDE-I-DNA adducts were significantly correlated to increased CYP1A1 activity in induced lung tissue but not in liver. The times to reach maximum adduct levels were similar for both controls and MC-induced rats in both lung and liver,and plasma albumin. The BPDE-I-albumin adducts reached a maximum level around 1 day after B[a]P exposure and could not be used as a reliable marker of the short term PAH exposure in this study. 相似文献
110.
Kohji Ishihara Nobuyoshi Nakajima Toshiyuki Itoh Hitomi Yamaguchi Kaoru Nakamura Tsutomu Furuya Hiroki Hamada 《Journal of Molecular Catalysis .B, Enzymatic》1999,7(5-6):307-310
The practical synthesis of vinyl p-coumarate (vinyl 4-hydroxycinnamate) and vinyl ferulate (vinyl 4-hydroxy-3-methoxycinnamate) was accomplished via a transesterification to the corresponding aromatic acid using vinyl acetate and a catalytic amount of PdCl2, followed by the lipase-catalyzed regioselective alcoholysis in EtOH. 相似文献