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991.
992.
Sterols are required for cell‐fate commitment and maintenance of the stomatal lineage in Arabidopsis
Pingping Qian Bing Han Edith Forestier Zhihong Hu Na Gao Wenwen Lu Hubert Schaller Jia Li Suiwen Hou 《The Plant journal : for cell and molecular biology》2013,74(6):1029-1044
Asymmetric cell division is important for regulating cell proliferation and fate determination during stomatal development in plants. Although genes that control asymmetric division and cell differentiation in stomatal development have been reported, regulators controlling the process from asymmetric division to cell differentiation remain poorly understood. Here, we report a weak allele (fk–J3158) of the Arabidopsis sterol C–14 reductase gene FACKEL (FK) that shows clusters of small cells and stomata in leaf epidermis, a common phenomenon that is often seen in mutants defective in stomatal asymmetric division. Interestingly, the physical asymmetry of these divisions appeared to be intact in fk mutants, but the cell‐fate asymmetry was greatly disturbed, suggesting that the FK pathway links these two crucial events in the process of asymmetric division. Sterol profile analysis revealed that the fk–J3158 mutation blocked downstream sterol production. Further investigation indicated that cyclopropylsterol isomerase1 (cpi1), sterol 14α–demethylase (cyp51A2) and hydra1 (hyd1) mutants, corresponding to enzymes in the same branch of the sterol biosynthetic pathway, displayed defective stomatal development phenotypes, similar to those observed for fk. Fenpropimorph, an inhibitor of the FK sterol C–14 reductase in Arabidopsis, also caused these abnormal small‐cell and stomata phenotypes in wild‐type leaves. Genetic experiments demonstrated that sterol biosynthesis is required for correct stomatal patterning, probably through an additional signaling pathway that has yet to be defined. Detailed analyses of time‐lapse cell division patterns, stomatal precursor cell division markers and DNA ploidy suggest that sterols are required to properly restrict cell proliferation, asymmetric fate specification, cell‐fate commitment and maintenance in the stomatal lineage cells. These events occur after physical asymmetric division of stomatal precursor cells. 相似文献
993.
Jeremy L. Yap Huabo Wang Angela Hu Jay Chauhan Kwan-Young Jung Robert B. Gharavi Edward V. Prochownik Steven Fletcher 《Bioorganic & medicinal chemistry letters》2013,23(1):370-374
A structure–activity relationship (SAR) study of the c-Myc (Myc) inhibitor 10074-G5 (N-([1,1′-biphenyl]-2-yl)-7-nitrobenzo[c][1,2,5]oxadiazol-4-amine, 1) – which targets a hydrophobic domain of the Myc oncoprotein that is flanked by arginine residues – was executed in order to determine its pharmacophore. Whilst the 7-nitrobenzofurazan was found to be critical for inhibitory activity, the ortho-biphenyl could be replaced with a para-carboxyphenyl group to furnish the new inhibitor JY-3-094 (3q). Around five times as potent as the lead with an IC50 of 33 μM for disruption of the Myc–Max heterodimer, JY-3-094 demonstrated excellent selectivity over Max–Max homodimers, with no apparent effect at 100 μM. Importantly, the carboxylic acid of JY-3-094 improves the physicochemical properties of the lead compound, which will facilitate the incorporation of additional hydrophobicity that might enhance Myc inhibitory activity further still. 相似文献
994.
Discovery of a small-molecule inhibitor and cellular probe of Keap1–Nrf2 protein–protein interaction
Longqin Hu Sadagopan Magesh Lin Chen Lili Wang Timothy A. Lewis Yu Chen Carol Khodier Daigo Inoyama Lesa J. Beamer Thomas J. Emge Jian Shen John E. Kerrigan Ah-Ng Tony Kong Sivaraman Dandapani Michelle Palmer Stuart L. Schreiber Benito Munoz 《Bioorganic & medicinal chemistry letters》2013,23(10):3039-3043
A high-throughput screen (HTS) of the MLPCN library using a homogenous fluorescence polarization assay identified a small molecule as a first-in-class direct inhibitor of Keap1–Nrf2 protein–protein interaction. The HTS hit has three chiral centers; a combination of flash and chiral chromatographic separation demonstrated that Keap1-binding activity resides predominantly in one stereoisomer (SRS)-5 designated as ML334 (LH601A), which is at least 100× more potent than the other stereoisomers. The stereochemistry of the four cis isomers was assigned using X-ray crystallography and confirmed using stereospecific synthesis. (SRS)-5 is functionally active in both an ARE gene reporter assay and an Nrf2 nuclear translocation assay. The stereospecific nature of binding between (SRS)-5 and Keap1 as well as the preliminary but tractable structure–activity relationships support its use as a lead for our ongoing optimization 相似文献
995.
Xin Hu Milos Vujanac Noel Southall C. Erec Stebbins 《Bioorganic & medicinal chemistry letters》2013,23(4):1056-1062
The bacterial protein tyrosine phosphatase YopH is an essential virulence determinant in Yersinia pestis and a potential antibacterial drug target. Here we report our studies of screening for small molecule inhibitors of YopH using both high throughput and in silico approaches. The identified inhibitors represent a diversity of chemotypes and novel pTyr mimetics, providing a starting point for further development and fragment-based design of multi-site binding inhibitors. We demonstrate that the applications of high throughput and virtual screening, when guided by structural binding mode analysis, is an effective approach for identifying potent and selective inhibitors of YopH and other protein phosphatases for rational drug design. 相似文献
996.
Damien Y. Duveau Xin Hu Martin J. Walsh Suneet Shukla Amanda P. Skoumbourdis Matthew B. Boxer Suresh V. Ambudkar Min Shen Craig J. Thomas 《Bioorganic & medicinal chemistry letters》2013,23(3):682-686
The importance of the trifluoromethyl group in the polypharmacological profile of nilotinib was investigated. Molecular editing of nilotinib led to the design, synthesis and biological evaluation of analogues where the trifluoromethyl group was replaced by a proton, fluorine and a methyl group. While these analogues were less active than nilotinib toward Abl, their activity toward Kit was comparable, with the monofluorinated analogue being the most active. Docking of nilotinib and of analogues 2a–c to the binding pocket of Abl and of Kit showed that the lack of shape complementarity in Kit is compensated by the stabilizing effect from its juxtamembrane region. 相似文献
997.
Simeon Bowers Ying-zi Xu Shendong Yuan Gary D. Probst Roy K. Hom Wayman Chan Andrei W. Konradi Hing L. Sham Yong L. Zhu Paul Beroza Hu Pan Eric Brecht Nanhua Yao Julie Lougheed Danny Tam Zhao Ren Lany Ruslim Michael P. Bova Dean R. Artis 《Bioorganic & medicinal chemistry letters》2013,23(7):2181-2186
The structure–activity relationship of a series of dihydroisoquinoline BACE-1 inhibitors is described. Application of structure-based design to screening hit 1 yielded sub-micromolar inhibitors. Replacement of the carboxylic acid of 1 was guided by X-ray crystallography, which allowed the replacement of a key water-mediated hydrogen bond. This work culminated in compounds such as 31, which possess good BACE-1 potency, excellent permeability and a low P-gp efflux ratio. 相似文献
998.
Guo-Wu Rao Cui Wang Jian Wang Zhen-Guo Zhao Wei-Xiao Hu 《Bioorganic & medicinal chemistry letters》2013,23(23):6474-6480
3,6-Diaryl-dihydro-1,2,4,5-tetrazine derivatives were synthesized and their structures were confirmed by single-crystal X-ray diffraction. Monosubstituted dihydrotetrazines are the 1,4-dihydro structure, but disubstituted dihydrotetrazines are the 1,2-dihydro structure. The results of further research indicated there may be a rearrangement during the synthesis process of disubstituted dihydrotetrazines. Their antitumor activities were evaluated against A-549 and P388 cells in vitro. The results showed several compounds to be endowed with cytotoxicity in the low micromolar range. Two compounds were highly effective against A-549 cell and IC50 values were 0.575 and 2.08 μM, respectively. Three-dimensional quantitative structure–activity relationship (3D-QSAR) studies of comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were carried out on 37 1,2,4,5-tetrazine derivatives with antitumor activity against A-549 cell. Models with good predictive abilities were generated with the cross validated q2 values for CoMFA and CoMSIA being 0.744 and 0.757, respectively. Conventional r2 values were 0.978 and 0.988, respectively, the predicted R2 values were 0.916 and 0.898, respectively. The results provide the tool for guiding the design and synthesis of novel and more potent tetrazine derivatives. 相似文献
999.
Li‐Yuan Wang Lin Zeng Yan‐Sheng Shi Zheng‐Liang Qiu Hua‐Hu Ye Xiao‐Fei Zhang Qing‐Bin Lu Michael Kosoy Wei Liu Wu‐Chun Cao 《Molecular ecology》2013,22(8):2118-2127
Bartonella quintana is a bacterium that causes a broad spectrum of diseases in humans including trench fever. Humans were previously considered to be the primary, if not the only, reservoir hosts for B. quintana. To identify the animal reservoir and extend our understanding of the ecological and evolutionary history of B. quintana, we examined blood samples from macaques and performed multilocus sequence typing (MLST) analysis. We demonstrated the prevalence of B. quintana infection was common in macaques from main primate centres in mainland China. Overall, 18.0% (59/328) of rhesus macaques and 12.7% (39/308) of cynomolgus macaques were found to be infected with B. quintana by blood culture and/or polymerase chain reaction. The infection was more frequently identified in juvenile and young monkeys compared with adult animals. In contrast with the relatively low level of sequence divergence of B. quintana reported in humans, our investigation revealed much higher genetic diversity in nonhuman primates. We identified 44 new nucleotide variable sites and 14 novel sequence types (STs) among the B. quintana isolates by MLST analysis. Some STs were found only in cynomolgus macaques, while some others were detected only in rhesus macaques, suggesting evidence of host‐cospeciation, which were further confirmed by phylogenetic analysis and Splits decomposition analysis. Our findings suggest that trench fever may primarily be a zoonotic disease with macaques as the natural hosts. 相似文献
1000.
Wen Yang Yang Hu Yu-Shun Yang Fei Zhang Yan-Bin Zhang Xiao-Liang Wang Jian-Feng Tang Wei-Qing Zhong Hai-Liang Zhu 《Bioorganic & medicinal chemistry》2013,21(5):1050-1063
Two series of novel naphthalin-containing pyrazoline derivatives C1–C14 and D1–D14 have been synthesized and evaluated for their EGFR/HER-2 inhibitory and anti-proliferation activities. Compound D14 displayed the most potent activity against EGFR and A549 cell line (IC50 = 0.05 μM and GI50 = 0.11 μM), being comparable with the positive control Erlotinib (IC50 = 0.03 μM and GI50 = 0.03 μM) and more potent than our previous compounds C0–A (IC50 = 5.31 μM and GI50 = 33.47 μM) and C0–B (IC50 = 0.09 μM and GI50 = 0.34 μM). Meanwhile, compound C14 displayed the most potent activity against HER-2 and MCF-7 cell line (IC50 = 0.88 μM and GI50 = 0.35 μM), being a little less potent than Erlotinib (IC50 = 0.16 μM and GI50 = 0.08 μM) but far more potent than C0–A (IC50 = 6.58 μM and GI50 = 27.62 μM) and C0–B (IC50 = 2.77 μM and GI50 = 3.79 μM). The docking simulation was performed to analyze the probable binding models and the QSAR models were built for reasonable design of EGFR/HER-2 inhibitors at present and in future. The structural modification of introducing naphthalin moiety reinforced the combination of our compounds and the receptor, resulting in progress of bioactivity. Moreover, the replacement of thiourea skeleton by using benzene ring resulted in the slight diversity of the two series towards specific targets. 相似文献