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133.
Leslie W. Tari Michael Trzoss Daniel C. Bensen Xiaoming Li Zhiyong Chen Thanh Lam Junhu Zhang Christopher J. Creighton Mark L. Cunningham Bryan Kwan Mark Stidham Karen J. Shaw Felice C. Lightstone Sergio E. Wong Toan B. Nguyen Jay Nix John Finn 《Bioorganic & medicinal chemistry letters》2013,23(5):1529-1536
The bacterial topoisomerases DNA gyrase (GyrB) and topoisomerase IV (ParE) are essential enzymes that control the topological state of DNA during replication. The high degree of conservation in the ATP-binding pockets of these enzymes make them appealing targets for broad-spectrum inhibitor development. A pyrrolopyrimidine scaffold was identified from a pharmacophore-based fragment screen with optimization potential. Structural characterization of inhibitor complexes conducted using selected GyrB/ParE orthologs aided in the identification of important steric, dynamic and compositional differences in the ATP-binding pockets of the targets, enabling the design of highly potent pyrrolopyrimidine inhibitors with broad enzymatic spectrum and dual targeting activity. 相似文献
134.
Stacy Van Epps Bryan Fiamengo Jeremy Edmunds Anna Ericsson Kristine Frank Michael Friedman Dawn George Jonathan George Eric Goedken Brian Kotecki Gloria Martinez Philip Merta Michael Morytko Shashank Shekhar Barbara Skinner Kent Stewart Jeffrey Voss Grier Wallace Neil Wishart 《Bioorganic & medicinal chemistry letters》2013,23(3):693-698
Interest in therapeutic kinase inhibitors continues to grow beyond success in oncology. To date, ATP-mimetic kinase inhibitors have focused primarily on monocyclic and bicyclic heterocyclic cores. We sought to expand on the repertoire of potential cores for kinase inhibition by exploring tricyclic variants of classical bicyclic hinge binding motifs such as pyrrolopyridine and pyrrolopyrazine. Herein we describe the syntheses of eight alternative tricyclic cores as well as in vitro screening results for representative kinases of potential therapeutic interest. 相似文献
135.
A road map for molecular ecology 总被引:1,自引:0,他引:1
Rose L. Andrew Louis Bernatchez Aurélie Bonin C. Alex. Buerkle Bryan C. Carstens Brent C. Emerson Dany Garant Tatiana Giraud Nolan C. Kane Sean M. Rogers Jon Slate Harry Smith Victoria L. Sork Graham N. Stone Timothy H. Vines Lisette Waits Alex Widmer Loren H. Rieseberg 《Molecular ecology》2013,22(10):2605-2626
The discipline of molecular ecology has undergone enormous changes since the journal bearing its name was launched approximately two decades ago. The field has seen great strides in analytical methods development, made groundbreaking discoveries and experienced a revolution in genotyping technology. Here, we provide brief perspectives on the main subdisciplines of molecular ecology, describe key questions and goals, discuss common challenges, predict future research directions and suggest research priorities for the next 20 years. 相似文献
136.
Ojas A. Namjoshi Zhi-jian Wang Sundari K. Rallapalli Edward Merle Johnson Yun-Teng Johnson Hanna Ng Joachim Ramerstorfer Zdravko Varagic Werner Sieghart Samarpan Majumder Bryan L. Roth James K. Rowlett James M. Cook 《Bioorganic & medicinal chemistry》2013,21(1):93-101
Selective modulation of specific benzodiazepine receptor (BzR) gamma amino butyric acid-A (GABAA) receptor ion channels has been identified as an important method for separating out the variety of pharmacological effects elicited by BzR-related drugs. Importantly, it has been demonstrated that both α2β(2/3)γ2 (α2BzR) and α3BzR (and/or α2/α3) BzR subtype selective ligands exhibit anxiolytic effects with little or no sedation. Previously we have identified several such ligands; however, three of our parent ligands exhibited significant metabolic liability in rodents in the form of a labile ester group. Here eight analogs are reported which were designed to circumvent this liability by utilizing a rational replacement of the ester moiety based on medicinal chemistry precedents. In a metabolic stability study using human liver microsomes, four compounds were found to undergo slower metabolic transformation, as compared to their corresponding ester analogs. These compounds were also evaluated in in vitro efficacy assays. Additionally, bioisostere 11 was evaluated in a rodent model of anxiety. It exhibited anxiolytic activity at doses of 10 and 100 mg/kg and was devoid of sedative properties. 相似文献
137.
Bryan D. Yestrepsky Yuanxi Xu Meghan E. Breen Xiaoqin Li Walajapet G. Rajeswaran Jenny G. Ryu Roderick J. Sorenson Yasuhiro Tsume Michael W. Wilson Wenpeng Zhang Duxin Sun Hongmin Sun Scott D. Larsen 《Bioorganic & medicinal chemistry》2013,21(7):1880-1897
Resistance to antibiotics is an increasingly dire threat to human health that warrants the development of new modes of treating infection. We recently identified 1 (CCG-2979) as an inhibitor of the expression of streptokinase, a critical virulence factor in Group A Streptococcus that endows blood-borne bacteria with fibrinolytic capabilities. In this report, we describe the synthesis and biological evaluation of a series of novel 5,6-dihydrobenzo[h]quinazolin-4(3H)-one analogs of 1 undertaken with the goal of improving the modest potency of the lead. In addition to achieving an over 35-fold increase in potency, we identified structural modifications that improve the solubility and metabolic stability of the scaffold. The efficacy of two new compounds 12c (CCG-203592) and 12k (CCG-205363) against biofilm formation in Staphylococcus aureus represents a promising additional mode of action for this novel class of compounds. 相似文献
138.
Youngjae Kim Jeeyeon Kim Jinsung Tae Bryan L. Roth Hyewhon Rhim Gyochang Keum Ghilsoo Nam Hyunah Choo 《Bioorganic & medicinal chemistry》2013,21(9):2568-2576
It has been reported that 5-HT7 receptors are promising targets of depression and neuropathic pain. 5-HT7 receptor antagonists have exhibited antidepressant-like profiles, while agonists have represented potential therapeutics for pain. In the course of our ongoing efforts to discover novel 5-HT7 modulators, we designed an arylpiperazine scaffold with a substituted biphenyl-2-ylmethyl group. A series of biphenyl-2-yl-arylpiperazinylmethanes were then prepared, which showed a broad spectrum of binding affinities to the 5-HT7 receptor depending upon the substituents attached to the biphenyl and aryl functionalities. Among those synthesized compounds, the compounds 1–24 and 1–26 showed the best binding affinities to the 5-HT7 receptor with Ki values of 43.0 and 46.0 nM, respectively. Structure–activity relationship study in conjunction with molecular docking study proposed that the 5-HT7 receptor might have two distinctive hydrophobic binding sites, one specific for aromatic 2-OCH3 substituents within the arylpiperazine and the other for biphenyl methoxy group. 相似文献
139.
Craig S. Charron Beverly A. Clevidence George A. Albaugh Matthew H. Kramer Bryan T. Vinyard John A. Milner Janet A. Novotny 《The Journal of nutritional biochemistry》2013,24(5):894-902
Allyl isothiocyanate (AITC) is a dietary component with possible anticancer effects, though much information about AITC and cancer has been obtained from cell studies. To investigate the effect of AITC on DNA integrity in vivo, a crossover study was conducted. Adults (n= 46) consumed AITC, AITC-rich vegetables [mustard and cabbage (M/C)] or a control treatment with a controlled diet for 10 days each. On day 11, volunteers provided blood and urine before and after consuming treatments. Volunteers were characterized for genotype for GSTM1 and GSTT1 (glutathione S-transferases) and XPD (DNA repair). DNA integrity in peripheral blood mononuclear cells was assessed by single-cell gel electrophoresis. Urine was analyzed for 8-oxo-7,8-dihydro-2’-deoxyguanosine (8-oxodG) and creatinine. Ten-day intake of neither AITC nor M/C resulted in statistically significant differences in DNA strand breaks [least squares mean (LSmean) % DNA in tail±S.E.M.: 4.8±0.6 for control, 5.7±0.7 for AITC, 5.3±0.6 for M/C] or urinary 8-oxodG (LSmean μg 8-oxodG/g creatinine±S.E.M.: 2.95±0.09 for control, 2.88±0.09 for AITC, 3.06±0.09 for M/C). Both AITC and M/C increased DNA strand breaks 3 h postconsumption (LSmean % DNA in tail±S.E.M.: 3.2±0.7 for control, 8.3±1.7 for AITC, 8.0±1.7 for M/C), and this difference disappeared at 6 h (4.2±0.9 for control, 5.7±1.2 for AITC, 5.5±1.2 for M/C). Genotypes for GSTM1, GSTT1 and XPD were not associated with treatment effects. In summary, DNA damage appeared to be induced in the short term by AITC and AITC-rich products, but that damage disappeared quickly, and neither AITC nor AITC-rich products affected DNA base excision repair. 相似文献
140.
Craig?SaleEmail author Guilherme?G.?Artioli Bruno?Gualano Bryan?Saunders Ruth?M.?Hobson Roger?C.?Harris 《Amino acids》2013,44(6):1477-1491
Carnosine was first discovered in skeletal muscle, where its concentration is higher than in any other tissue. This, along with an understanding of its role as an intracellular pH buffer has made it a dipeptide of interest for the athletic population with its potential to increase high-intensity exercise performance and capacity. The ability to increase muscle carnosine levels via β-alanine supplementation has spawned a new area of research into its use as an ergogenic aid. The current evidence base relating to the use of β-alanine as an ergogenic aid is reviewed here, alongside our current thoughts on the potential mechanism(s) to support any effect. There is also some emerging evidence for a potential therapeutic role for carnosine, with this potential being, at least theoretically, shown in ageing, neurological diseases, diabetes and cancer. The currently available evidence to support this potential therapeutic role is also reviewed here, as are the potential limitations of its use for these purposes, which mainly focusses on issues surrounding carnosine bioavailability. 相似文献