排序方式: 共有30条查询结果,搜索用时 0 毫秒
1.
Yan Zhang Orgil Elbegdorj Yunyun Yuan Irina O. Beletskaya Dana E. Selley 《Bioorganic & medicinal chemistry letters》2013,23(13):3719-3722
Isosterism is commonly used in drug discovery and development to address stability, selectivity, toxicity, pharmacokinetics, and efficacy issues. A series of 14-O-substituted naltrexone derivatives were identified as potent mu opioid receptor (MOR) antagonists with improved selectivity over the kappa opioid receptor (KOR) and the delta opioid receptor (DOR), compared to naltrexone. Since esters are not metabolically very stable under typical physiological conditions, their corresponding amide analogs were thus synthesized and biologically evaluated. Unlike their isosteres, most of these novel ligands seem to be dually selective for the MOR and the KOR over the DOR. The restricted flexibility of the amide bond linkage might be responsible for their altered selectivity profile. However, the majority of the 14-N-substituted naltrexone derivatives produced marginal or no MOR stimulation in the 35S-GTP[γS] assay, which resembled their ester analogs. The current study thus indicated that the 14-substituted naltrexone isosteres are not bioisosteres since they have distinctive pharmacological profile with the regard to their opioid receptor binding affinity and selectivity. 相似文献
2.
Survival of Male Patients with Incontinentia Pigmenti Carrying a Lethal Mutation Can Be Explained by Somatic Mosaicism or Klinefelter Syndrome 总被引:2,自引:0,他引:2
下载免费PDF全文
![点击此处可从《American journal of human genetics》网站下载免费的PDF全文](/ch/ext_images/free.gif)
The International IP Consortium 《American journal of human genetics》2001,69(6):1210-1217
Incontinentia pigmenti (IP), or "Bloch-Sulzberger syndrome," is an X-linked dominant disorder characterized by abnormalities of skin, teeth, hair, and eyes; skewed X-inactivation; and recurrent miscarriages of male fetuses. IP results from mutations in the gene for NF-kappaB essential modulator (NEMO), with deletion of exons 4-10 of NEMO accounting for >80% of new mutations. Male fetuses inheriting this mutation and other "null" mutations of NEMO usually die in utero. Less deleterious mutations can result in survival of males subjects, but with ectodermal dysplasia and immunodeficiency. Male patients with skin, dental, and ocular abnormalities typical of those seen in female patients with IP (without immunodeficiency) are rare. We investigated four male patients with clinical hallmarks of IP. All four were found to carry the deletion normally associated with male lethality in utero. Survival in one patient is explained by a 47,XXY karyotype and skewed X inactivation. Three other patients possess a normal 46,XY karyotype. We demonstrate that these patients have both wild-type and deleted copies of the NEMO gene and are therefore mosaic for the common mutation. Therefore, the repeat-mediated rearrangement leading to the common deletion does not require meiotic division. Hypomorphic alleles, a 47,XXY karyotype, and somatic mosaicism therefore represent three mechanisms for survival of males carrying a NEMO mutation. 相似文献
3.
Zakharova MV Beletskaya IV Denjmukhametov MM Yurkova TV Semenova LM Shlyapnikov MG Solonin AS 《Molecular genetics and genomics : MGG》2002,267(2):171-178
The primary structures of the plasmids pECL18 (5571 bp) and pKPN2 (4196 bp) from Escherichia coli and Klebsiella pneumoniae, respectively, which carry genes for a Type II restriction-modification system (RMS2) with the specificity 5'-CCNGG-3', were determined in order to elucidate the structural relationship between them. The data suggest a possible role for recombination events at bom (basis of mobility) regions and the sites of resolution of multimer plasmid forms (so-called cer sequences) in the structural evolution of multicopy plasmids. Analysis of the sequences of pECL18 and pKPN2 showed that the genes for RM* Ecl18kI and RM* Kpn2kI, and the sequences of the rep (replication) regions in the two plasmids, are almost identical. In both plasmids, these regions are localized between the bom regions and the cer sites. The rest of the pECL18 sequence is almost identical to that of the mob (mobilization) region of ColE1, and the corresponding segment of pKPN2 is almost identical to part of pHS-2 from Shigella flexneri. The difference in primary structures results in different mobilization properties of pECL18 and pKPN2. The complete sequences of pECL18, pKPN2 and the pairwise comparison of the sequences of pECL18, pKPN2, ColE1 and pHS-2 suggest that plasmids may exchange DNA units via site-specific recombination events at bom and cer sites. In the course of BLASTN database searches using the cer sites of pECL18 and pKPN2 as queries, we found twenty cer sites of natural plasmids. Alignment of these sequences reveals that they fall into two classes. The plasmids in each group possess related segments between their cer and bom sites. 相似文献
4.
Journal of Ichthyology - The paper reports the first find of the marbled spinefoot Siganus rivulatus Forsskål et Niebuhr, 1775, which is a new species for the Black Sea, at the southeastern... 相似文献
5.
E. V. Moiseeva N. R. Kuznetsova E. V. Svirshchevskaya N. V. Bovin N. S. Sitnikov A. S. Shavyrin I. P. Beletskaya S. Combes A. Yu. Fedorov E. L. Vodovozova 《Biochemistry (Moscow) Supplemental Series B: Biomedical Chemistry》2011,5(3):276-283
The antimitotic agent combretastatin A-4 (CA-4) has been recently proposed as an antivascular agent for anticancer therapy.
In order to reduce systemic toxicity by means of administration in liposome formulations, new lipophilic prodrugs, oleic derivatives
of CA-4 and its 4-arylcoumarin analogue (CA4-Ole and ArC-Ole, respectively), have been synthesized in this study. Liposomes
with mean diameter of 100 nm prepared on the basis of egg phosphatidylcholine and baker’s yeast phosphatidylinositol quantitatively
included up to 15 mol% of CA4-Ole, or 7 mol% of ArC-Ole. To achieve targeting to neovascular endothelium prodrug bearing liposomes
decorated with the tetrasaccharide selectin ligand Sialyl Lewis X (SiaLeX) have been also prepared. The antitumor activity
was studied in vivo using the model of slow-growing mouse breast cancer. Under the dose used (22 mg/kg) and the administration
protocol (four injections, one per a week, starting from the appearance of palpable tumors) cytostatic CA-4 did not reveal
any anticancer effect; moreover, it even stimulated tumor growth. The liposome formulations of CA4-Ole did not demonstrate
such stimulation. However, to achieve a pronounced antitumor effect, the number of injections of liposomes should be apparently
increased. The cytotoxic activity of a novel antimitotic agent ArC was one order of magnitude lower in the human breast carcinoma
cell culture in vitro. Nevertheless, in vivo in the mouse model of breast cancer the antitumor effect of this compound corresponded
to the double equivalent dose of CA-4. The results demonstrate perspectives of SiaLeX-liposomes loaded with ArC-Ole: the preparation partially inhibited tumor growth already after the second injection. Thus,
subsequent optimization of doses and regimens of administration both for ArC and liposomal ArC-Ole formulations are needed. 相似文献
6.
The level of proteinase activity and the ratio of proteinases I and II, secreted byAspergillus terreus, a cellulase producer, was followed during its growth on media containing various carbon sources. Correlation was found between
the level of proteinase secretion and the rate of change of the cellulase complex spectrum. The extracellular proteolytic
system ofA. terreus was presented mainly by proteinase II (metalloproteinase) during cultivation under conditions favoring fast accumulation
of low-molar mass cellulases. The results indicate that proteinase II could be responsible for the limited proteolysis of
high-molar mass cellulases ofA. terreus into smaller enzymes of the cellulolytic complex, thus changing their substrate specificity. 相似文献
7.
S. LUYSSAERT P. CIAIS S. L. PIAO E.‐D. SCHULZE M. JUNG S. ZAEHLE M. J. SCHELHAAS M. REICHSTEIN G. CHURKINA D. PAPALE G. ABRIL C. BEER J. GRACE D. LOUSTAU G. MATTEUCCI F. MAGNANI G. J. NABUURS H. VERBEECK M. SULKAVA G. R.
Van Der WERF I. A. JANSSENS members of the CARBOEUROPE‐IP SYNTHESIS TEAM 《Global Change Biology》2010,16(5):1429-1450
We present a new synthesis, based on a suite of complementary approaches, of the primary production and carbon sink in forests of the 25 member states of the European Union (EU‐25) during 1990–2005. Upscaled terrestrial observations and model‐based approaches agree within 25% on the mean net primary production (NPP) of forests, i.e. 520±75 g C m?2 yr?1 over a forest area of 1.32 × 106 km2 to 1.55 × 106 km2 (EU‐25). New estimates of the mean long‐term carbon forest sink (net biome production, NBP) of EU‐25 forests amounts 75±20 g C m?2 yr?1. The ratio of NBP to NPP is 0.15±0.05. Estimates of the fate of the carbon inputs via NPP in wood harvests, forest fires, losses to lakes and rivers and heterotrophic respiration remain uncertain, which explains the considerable uncertainty of NBP. Inventory‐based assessments and assumptions suggest that 29±15% of the NBP (i.e., 22 g C m?2 yr?1) is sequestered in the forest soil, but large uncertainty remains concerning the drivers and future of the soil organic carbon. The remaining 71±15% of the NBP (i.e., 53 g C m?2 yr?1) is realized as woody biomass increments. In the EU‐25, the relatively large forest NBP is thought to be the result of a sustained difference between NPP, which increased during the past decades, and carbon losses primarily by harvest and heterotrophic respiration, which increased less over the same period. 相似文献
8.
Nucleotide sequence of the genes for tryptophan synthase in Pseudomonas aeruginosa 总被引:17,自引:0,他引:17
We have determined the DNA sequence of the two adjacent genes for the alpha
and beta chains of tryptophan synthase in Pseudomonas aeruginosa, along
with 34 5'-flanking and 799 3'-flanking base pairs. The gene order is trpBA
as predicted from earlier genetic studies, and the two cistrons overlap by
4 bp; a ribosome binding site for the second gene is evident in the coding
sequence of the first gene. We have also determined the location of three
large deletions eliminating portions of each gene. A detailed comparison of
the deduced P. aeruginosa amino acid sequence with those published for E.
coli, Bacillus subtilis, and Saccharomyces cerevisiae shows much similarity
throughout the beta and most of the alpha subunit. Most of the residues
implicated by chemical modification or mutation as being critical for
enzymatic activity are conserved, along with many others, suggesting that
three-dimensional structure has remained largely constant during evolution.
We also report the construction of a recombinant plasmid that overproduces
a slightly modified alpha subunit from P. aeruginosa that can form a
functionally effective multimer with normal E. coli beta 2 subunit in vivo.
相似文献
9.
M.?V.?ZakharovaEmail author I.?V.?Beletskaya D.?V.?Bolovin T.?V.?Yurkova L.?M.?Semenova A.?S.?Solonin 《Molecular genetics and genomics : MGG》2004,270(5):415-419
We have studied the recombination of plasmids bearing bom and cer sites. The bom (basis of mobilization) site is required for conjugative transfer, while the cer (ColE1 resolution) site is involved in the resolution of plasmid multimers, which increases plasmid stability. We constructed a pair of parent plasmids in such a way as to allow us select clones containing recombinant plasmids directly. Clone selection was based on the McrA sensitivity of recipient host DNA modified by M. Ecl18kI, which is encoded by one of the parent plasmids. The recombinant plasmid contains segments originating from both parental DNAs, which are bounded by bom and cer sites. Its structure is in accordance with our previously proposed model for recombination mediated by bom and cer sequences. The frequency of recombinant plasmid formation coincided with the frequency of recombination at the bom site. We also show that bom-mediated recombination in trans, unlike in cis, is independent of other genetic determinants on the conjugative plasmids.Communicated by W. Goebel 相似文献
10.
Sergey A. Mitchenko Eugeniy V. Khomutov Alexander N. Vdovichenko Igor V. Zhikharev Anatoliy F. Popov Irina P. Beletskaya 《Inorganica chimica acta》2001,320(1-2):38-46
Mechanically pre-activated K2PtCl4 salt consumes methyl iodide producing methyl chloride at room temperature. The reaction mechanism includes the following steps sequence: oxidative addition of methyl iodide to platinum(II) complexes with intermediate formation of methyl platinum(IV) complexes and further decomposition of the latter in the course of innersphere reductive elimination yielding methyl chloride. The first step of the reaction proceeds owing to the assistance of active centers regenerated in the course of each event of MeI into MeCl transformation taking part in the chain halogen substitution process. It could be assumed that the role of active centers is played by coordinatively unsaturated platinum(II) complexes located on the surface. These species bearing a positive efficient charge can render electrophilic assistance for the nucleophilic substitution. The chain termination can be caused by recombination of coordinatively unsaturated platinum(II) complexes and interstitial chloride ions forming an inactive K2PtCl4 complex. 相似文献