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991.
992.
Zheng Zhang Sriram Jakkaraju Joy Blain Kenneth Gogol Lei Zhao Robert C. Hartley Courtney A. Karlsson Bart L. Staker Thomas E. Edwards Lance J. Stewart Peter J. Myler Michael Clare Darren W. Begley James R. Horn Timothy J. Hagen 《Bioorganic & medicinal chemistry letters》2013,23(24):6860-6863
Published biological data suggest that the methyl erythritol phosphate (MEP) pathway, a non-mevalonate isoprenoid biosynthetic pathway, is essential for certain bacteria and other infectious disease organisms. One highly conserved enzyme in the MEP pathway is 2C-methyl-d-erythritol 2,4-cyclodiphosphate synthase (IspF). Fragment-bound complexes of IspF from Burkholderia pseudomallei were used to design and synthesize a series of molecules linking the cytidine moiety to different zinc pocket fragment binders. Testing by surface plasmon resonance (SPR) found one molecule in the series to possess binding affinity equal to that of cytidine diphosphate, despite lacking any metal-coordinating phosphate groups. Close inspection of the SPR data suggest different binding stoichiometries between IspF and test compounds. Crystallographic analysis shows important variations between the binding mode of one synthesized compound and the pose of the bound fragment from which it was designed. The binding modes of these molecules add to our structural knowledge base for IspF and suggest future refinements in this compound series. 相似文献
993.
Ke-Wu Yang Lei Feng Shao-Kang Yang Mahesh Aitha Alecander E. LaCuran Peter Oelschlaeger Michael W. Crowder 《Bioorganic & medicinal chemistry letters》2013,23(21):5855-5859
In an effort to test whether a transition state analog is an inhibitor of the metallo-β-lactamases, a phospholactam analog of carbapenem has been synthesized and characterized. The phospholactam 1 proved to be a weak, time-dependent inhibitor of IMP-1 (70%), CcrA (70%), L1 (70%), NDM-1 (53%), and Bla2 (94%) at an inhibitor concentration of 100 μM. The phospholactam 1 activated ImiS and BcII at the same concentration. Docking studies were used to explain binding and to offer suggestions for modifications to the phospholactam scaffold to improve binding affinities. 相似文献
994.
Lei Ding Feng Tang Wei Huang Qiu Jin Han Shen Ping Wei 《Bioorganic & medicinal chemistry letters》2013,23(20):5630-5633
A novel series of 3-pyrrolo[b]cyclohexylene-2-dihydroindolinone derivatives targeting VEGFR-2, PDGFR-β and c-Kit kinases were designed and synthesized. The molecular design was based on the SAR features of indolin-2-ones as kinase inhibitors. SAR study of the series allowed us to identify compounds possessing more potent inhibitory activities against the three kinases than sunitinb with IC50 values in the low nanomolar range in vitro. Additionally, some compounds also showed favorable antiproliferative activities against a panel of cancer cell lines (BXPC-3, T24, BGC, HEPG2 and HT29). 相似文献
995.
Li-Ping Shi Kun-Ming Jiang Jun-Jie Jiang Yi Jin Yun-Hai Tao Ke Li Xing-Hong Wang Jun Lin 《Bioorganic & medicinal chemistry letters》2013,23(21):5958-5963
A novel series of polyhalobenzonitrile quinazolin-4(3H)-one derivatives were synthesized and characterized by NMR, IR, MS, and HRMS spectra. All of the newly prepared compounds were screened for antimicrobial activities against four strains of bacteria (Gram-positive bacterial: Staphylococcus aureus and Bacillus cereus; Gram-negative bacterial: Escherichia coli and Pseudomonas aeruginosa) and one strain of fungi (Candida albicans). Among the synthesized compounds, 5-(dimethylamino)-8-(2,4,5-trichloro-isophthalonitrile) quinazolin-4(3H)-one (7k) exhibited significant activity towards Gram-positive bacterial, Gram-negative bacterial, and the fungi strains. The MIC (0.8–3.3 μg/mL) and MBC (2.6–7.8 μg/mL) for this compound were close to those of nofloxacin, chlorothalonil, and fluconazole, making it the most potent antimicrobial agents in the series. 相似文献
996.
Zhongli Gao William J. Hurst Etienne Guillot Werngard Czechtizky Ulrike Lukasczyk Raisa Nagorny Marie-Pierre Pruniaux Lothar Schwink Juan Antonio Sanchez Siegfried Stengelin Lei Tang Irvin Winkler James A. Hendrix Pascal G. George 《Bioorganic & medicinal chemistry letters》2013,23(11):3416-3420
A series of structurally novel aryl ureas was derived from optimization of the HTS lead as selective histamine H3 receptor (H3R) antagonists. The SAR was explored and the data obtained set up the starting point and foundation for further optimization. The most potent tool compounds, as exemplified by compounds 2l, 5b, 5d, and 5e, displayed antagonism potencies in the subnanomolar range in in vitro human-H3R FLIPR assays and rhesus monkey H3R binding assays. 相似文献
997.
Youguang Zheng Ming Zheng Xin Ling Yi Liu Yunsheng Xue Lin An Ning Gu Min Jin 《Bioorganic & medicinal chemistry letters》2013,23(12):3523-3530
Novel pyrazole–benzimidazole derivatives have been designed and synthesized. The entire target compounds were determined against cancer cell lines U937, K562, A549, LoVo and HT29 and were screened for Aurora A/B kinase inhibitory activity in vitro. The compounds 7a, 7b, 7i, 7k and 7l demonstrated significant cancer cell lines and Aurora A/B kinase inhibitory activities. Molecular modeling studies suggested the derivatives have bound in the active site of Aurora A kinase through the formation of four hydrogen bonds. Quantum chemical studies were carried out on these compounds to understand the structural features essential for activity. The cellular activity of 7k was also tested by immunofluorescence. 相似文献
998.
Kevin Anderson Yi Chen Zhi Chen Romyr Dominique Kelli Glenn Yang He Cheryl Janson Kin-Chun Luk Christine Lukacs Ann Polonskaia Qi Qiao Aruna Railkar Pamela Rossman Hongmao Sun Qing Xiang Masha Vilenchik Peter Wovkulich Xiaolei Zhang 《Bioorganic & medicinal chemistry letters》2013,23(24):6610-6615
DYRK1B is a kinase over-expressed in certain cancer cells (including colon, ovarian, pancreatic, etc.). Recent publications have demonstrated inhibition of DYRK1B could be an attractive target for cancer therapy. From a data-mining effort, the team has discovered analogues of pyrido[2,3-d]pyrimidines as potent enantio-selective inhibitors of DYRK1B. Cells treated with a tool compound from this series showed the same cellular effects as down regulation of DYRK1B with siRNA. Such effects are consistent with the proposed mechanism of action. Progress of the SAR study is presented. 相似文献
999.
Xianwen Cao Jing Jiang Shoude Zhang Lili Zhu Juan Zou Yanyan Diao Weilie Xiao Lei Shan Handong Sun Weidong Zhang Jin Huang Honglin Li 《Bioorganic & medicinal chemistry letters》2013,23(11):3329-3333
Eleven compounds were identified as estrogen receptor modulators from an in-house natural product database (NPD) by structure-based virtual screening for ERα and ERβ. Among them, 3 compounds were confirmed as ER agonists and 8 compounds were confirmed as ER antagonists by yeast two-hybrid (Y2H) assay, with EC50 values ranging from several micromolar to 100 micromolar. In this study, a novel series of cycloartane triterpenoids isolated from Schisandra glaucescens Diels was found to have ER antagonistic effect, the most potent antagonist of which exhibited activity with EC50 value of 2.55 and 4.68 μM for ERα and ERβ, respectively. Moreover, the types of modulation and subtype selectivity were also investigated through molecular docking simulation. 相似文献
1000.
Ectopic overexpression of porcine DGAT1 increases intramuscular fat content in mouse skeletal muscle
Ting Li Dequan Xu Bo Zuo Minggang Lei Yuanzhu Xiong Hongxing Chen Yanhong Zhou Xiaojie Wu 《Transgenic research》2013,22(1):187-194
The microsomal enzyme 1, 2-acyl CoA: diacylglyceroltransferase-1 (DGAT1) plays an important role in triglyceride storage in adipose tissue and expresses in skeletal muscle as well. The primary goal of the present study was to investigate the effect of porcine DGAT1 on intramuscular fat (IMF) content of transgenic mice produced by pronuclear microinjection with muscle specific promoter of porcine muscle creatine kinase (MCK). In normal chow-fed diet, 4 month-old male transgenic mice expressed more DGAT1, ACC1, UCP1, and FABP4 mRNAs and proteins in skeletal muscle than control mice by real-time PCR and western blot. No significant changes were detected for ACC2, CD36, ADRP, PPAR gamma and LPL. Triacylglycerol assay and soleus muscle sections showed overexpression of porcine DGAT1 in skeletal muscle increased intramyocellular triglyceride and percent of the total cell surface covered by lipid droplets. Thus, upregulation of porcine DGAT1 in skeletal muscle increases IMF content. The present study may further serve to develop transgenic pigs with higher IMF content and improved meat quality. 相似文献