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951.
Deepak Bhasin Jonathan P. Etter Somsundaram N. Chettiar May Mok Pui-Kai Li 《Bioorganic & medicinal chemistry letters》2013,23(24):6864-6867
STAT3 is constitutively active in a large variety of cancers. The search for STAT3 inhibitors led to the discoveries of LLLs 3 and 12, which are substituted anthraquinones. LLL12 is an extremely potent compound that exhibits high levels of antiproliferative activity. Herein the synthesis and evaluation of compounds containing either an anthraquinone or 1,4-naphthoquinone moiety are reported. Analogs were evaluated in several cancer cell lines. Interestingly, it was found that the anthraquinones did not follow the same trends as the 1,4-naphthoquinones in regards to potency. LLL12, which contains a sulfonamide at position 1, was found to be the most potent of the anthraquinones. In contrast, the methyl ketone and methyl ester derivatives (LLLs 3.1 and 5.1) were found to be the most potent of the 1,4-naphthoquinones. Selected 1,4-naphthoquinones were also evaluated in the STAT3 fluorescence polarization assay in order to evaluate their abilities to bind to the STAT3 SH2 domain. They were found to have similar affinities, and their activities suggest that STAT3 is one of their molecular targets. 相似文献
952.
Suniti Misra Shibnath Ghatak Neha Patil Prasad Dandawate Vinita Ambike Shreelekha Adsule Deepak Unni K. Venkateswara Swamy Subhash Padhye 《Bioorganic & medicinal chemistry》2013,21(9):2551-2559
Cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) enzyme have been found to play a role in promoting growth in colon cancer cell lines. The di-tert-butyl phenol class of compounds has been found to inhibit both COX-2 and 5-LOX enzymes with proven effectiveness in arresting tumor growth. In the present study, the structural analogs of 2,6 di-tert-butyl-p-benzoquinone (BQ) appended with hydrazide side chain were found to inhibit COX-2 and 5-LOX enzymes at micromolar concentrations. Molecular docking of the compounds into COX-2 and 5-LOX protein cavities indicated strong binding interactions supporting the observed cytototoxicities. The signaling interaction between endogenous hyaluronan and CD44 has been shown to regulate COX-2 activities through ErbB2 receptor tyrosine kinase (RTK) activation. In the present studies it has been observed for the first time, that three of our COX/5-LOX dual inhibitors inhibit proliferation upon hydrazide substitution and prevent the activity of pro-angiogenic factors in HCA-7, HT-29, Apc10.1 cells as well as the hyaluronan synthase-2 (Has2) enzyme over-expressed in colon cancer cells, through inhibition of the hyaluronan/CD44v6 cell survival pathway. Since there is a substantial enhancement in the antiproliferative activities of these compounds upon hydrazide substitution, the present work opens up new opportunities for evolving novel active compounds of BQ series for inhibiting colon cancer. 相似文献
953.
Chattopadhyay MK Fernandez C Sharma D McPhie P Masison DC 《Biochemical and biophysical research communications》2011,(2):177-182
Protein kinase C (PKC) δ plays an important role in cellular proliferation and apoptosis. The catalytic fragment of PKCδ generated by caspase-dependent cleavage is essential for the initiation of etoposide-induced apoptosis. In this study, we identified a novel mouse PKCδ isoform named PKCδIX (Genebank Accession No. HQ840432). PKCδIX is generated by alternative splicing and is ubiquitously expressed, as seen in its full-length PKCδ. PKCδIX lacks the C1 domain, the caspase 3 cleavage site, and the ATP binding site but preserves an almost intact c-terminal catalytic domain and a nuclear localization signal (NLS). The structural characteristics of PKCδIX provided a possibility that this PKCδ isozyme functions as a novel dominant-negative form for PKCδ due to its lack of the ATP-binding domain that is required for the kinase activity of PKCδ. Indeed, overexpression of PKCδIX significantly inhibited etoposide-induced apoptosis in NIH3T3 cells. In addition, an in vitro kinase assay showed that recombinant PKCδIX protein could competitively inhibit the kinase activity of PKCδ. We conclude that PKCδIX can function as a natural dominant-negative inhibitor of PKCδ in vivo. 相似文献
954.
This study illustrates the genetic diversity and relationships within and among six Indian sheep breeds of the northwestern arid region of Rajasthan, based on microsatellite markers. The range of allele diversity was 7.72-9.56, and gene diversity was 0.686-0.766, revealing that these breeds possessed substantial amounts of genetic diversity. Positive F (IS) values suggested a deficit of heterozygotes in all six breeds. Despite the declining status of the Marwari, Chokla, Jaisalmeri, Magra and Pugal breeds, an absence of a recent genetic bottleneck was evident from the data. The genetic differentiation estimate (F (ST)?=?6.1%) suggested low levels of differentiation between the breeds. Genetic distance estimates revealed a close relationship between the Magra-Pugal and Nali-Jaisalmeri breed pairs. This information forms a framework for designing genetic management and conservation programs for these valuable ovine breeds. 相似文献
955.
Lanktree MB Guo Y Murtaza M Glessner JT Bailey SD Onland-Moret NC Lettre G Ongen H Rajagopalan R Johnson T Shen H Nelson CP Klopp N Baumert J Padmanabhan S Pankratz N Pankow JS Shah S Taylor K Barnard J Peters BJ Maloney CM Lobmeyer MT Stanton A Zafarmand MH Romaine SP Mehta A van Iperen EP Gong Y Price TS Smith EN Kim CE Li YR Asselbergs FW Atwood LD Bailey KM Bhatt D Bauer F Behr ER Bhangale T Boer JM Boehm BO Bradfield JP Brown M Braund PS Burton PR Carty C Chandrupatla HR Chen W Connell J 《American journal of human genetics》2011,(1):688-18
Height is a classic complex trait with common variants in a growing list of genes known to contribute to the phenotype. Using a genecentric genotyping array targeted toward cardiovascular-related loci, comprising 49,320 SNPs across approximately 2000 loci, we evaluated the association of common and uncommon SNPs with adult height in 114,223 individuals from 47 studies and six ethnicities. A total of 64 loci contained a SNP associated with height at array-wide significance (p < 2.4 × 10−6), with 42 loci surpassing the conventional genome-wide significance threshold (p < 5 × 10−8). Common variants with minor allele frequencies greater than 5% were observed to be associated with height in 37 previously reported loci. In individuals of European ancestry, uncommon SNPs in IL11 and SMAD3, which would not be genotyped with the use of standard genome-wide genotyping arrays, were strongly associated with height (p < 3 × 10−11). Conditional analysis within associated regions revealed five additional variants associated with height independent of lead SNPs within the locus, suggesting allelic heterogeneity. Although underpowered to replicate findings from individuals of European ancestry, the direction of effect of associated variants was largely consistent in African American, South Asian, and Hispanic populations. Overall, we show that dense coverage of genes for uncommon SNPs, coupled with large-scale meta-analysis, can successfully identify additional variants associated with a common complex trait. 相似文献
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960.
R. Bhatia K. P. Singh T. R. Sharma Tripta Jhang 《Plant Cell, Tissue and Organ Culture》2011,104(1):131-135
The genetic fidelity of in vitro-raised gerbera clones was assessed by using random amplified polymorphic DNA (RAPD) and inter-simple
sequence repeat (ISSR) markers. Out of 35 RAPD and 32 ISSR primers screened, only 12 RAPD and 10 ISSR primers produced clear,
reproducible and scorable bands. The 12 RAPD primers produced 54 distinct and scorable bands, with an average of 4.5 bands
per primer. The number of scorable bands for ISSR primers varied from 3 (ISSR-14) to 9 (ISSR-07), with an average of 5.5 bands
per primer. The number of bands generated per primer was greater in ISSR than RAPD. All banding profiles from micropropagated
plants were monomorphic and similar to those of the mother plant. A similarity matrix based on Jaccard’s coefficient revealed
that the pair-wise value between the mother and the in vitro-raised plantlets was 1, indicating 100% similarity. This confirmed
the true-to-type nature of the in vitro-raised clones. 相似文献