共查询到20条相似文献,搜索用时 15 毫秒
1.
Patrícia Bacalhau Luís Fernandes M. Rosário Martins Fátima Candeias Elisabete P. Carreiro Óscar López A. Teresa Caldeira Jane Totobenazara Rita C. Guedes Anthony J. Burke 《Bioorganic & medicinal chemistry》2019,27(2):354-363
From a screening study of various potential inhibitors for cholinesterases (ChEs), compound (rac)-1 (4-((3-hydroxy-2-oxo-3-phenylindolin-1-yl) methyl) piperidin-1-ium chloride) showed an IC50 of 18?μM for butyrylcholinesterase (BuChE). Herein we present a toxicological and pharmacological evaluation of (rac)-1 to determine its potential for use as an alternative ChE inhibitor for the treatment of Alzheimer’s disease. The strategy adopted included in vivo and ex vivo studies with mouse models, Molecular Modelling and Saturation Transfer Difference (STD) NMR studies.Preliminary molecular docking studies were conducted with both (R) and (S)-1 with acetylcholinesterase (AChE) and BuChE, prior to advancing to the mouse model, and indeed favorable interactions were observed, with (R)-1 showing the best binding with AChE and (S)-1 with BuChE. STD-NMR studies were used to successfully validate these results. Toxicological studies were also conducted using the Artemia salina model, with donepezil as reference. It was found that in the in vivo mouse studies that (rac)-1 presented a slightly better inhibition of AChE (0.096?µmol.min?1.mg?1) than donepezil (0.112?µmol.min?1.mg?1) and the same level of inhibition for BuChE as donepezil (0.014?µmol.min?1.mg?1). 相似文献
2.
Sandipan Roy Chowdhury Steven Kennedy Kai Zhu Rama Mishra Patrick Chuong Alyssa-uyen Nguyen Stefan G. Kathman Alexander V. Statsyuk 《Bioorganic & medicinal chemistry letters》2019,29(1):36-39
Here we present a virtual docking screen of 1648 commercially available covalent fragments, and identified covalent inhibitors of cysteine protease cathepsin L. These inhibitors did not inhibit closely related protease cathepsin B. Thus, we have established virtual docking of covalent fragments as an approach to discover covalent enzyme inhibitors. 相似文献
3.
Eliot L. Osher Francisco Castillo Nagarajan Elumalai Michael J. Waring Garry Pairaudeau Ali Tavassoli 《Bioorganic & medicinal chemistry》2018,26(11):3034-3038
We report an inhibitor of the homodimeric protein-protein interaction of the BCL6 oncoprotein, identified from a genetically encoded SICLOPPS library of 3.2 million cyclic hexapeptides in combination with a bacterial reverse two-hybrid system. This cyclic peptide is shown to bind the BTB domain of BCL6, disrupts its homodimerization, and subsequent binding of the SMRT2 corepressor peptide. 相似文献
4.
5.
6.
Fluxe A Wu S Sheffer JB Janusz JM Murawsky M Fadayel GM Fang B Hare M Djandjighian L 《Bioorganic & medicinal chemistry letters》2006,16(22):5855-5858
A novel class of tetrahydroindolone-derived carbamates has been discovered whose members are potent Kv1.5 blockers. The in vitro data show that compounds 6 and 29 are quite potent. They are also very selective over hERG (>450-fold) and L-type calcium channels (>450-fold). 相似文献
7.
Suyoung Yoon Dongxu Zuo Jong Hyun Kim Ina Yoon Jihyae Ann Sung-Eun Kim Dasol Cho Won Kyung Kim Sangkook Lee Jiyoun Lee Sunghoon Kim Jeewoo Lee 《Bioorganic & medicinal chemistry》2018,26(14):4073-4079
According to recent studies, leucyl-tRNA synthetase (LRS) acts as a leucine sensor and modulates the activation of the mammalian target of rapamycin complex 1 (mTORC1) activation. Because overactive mTORC1 is associated with several diseases, including colon cancer, LRS-targeted mTORC1 inhibitors represent a potential option for anti-cancer therapy. In this work, we developed a series of simplified leucyladenylate sulfamate analogues that contain the N-(3-chloro-4-fluorophenyl)quinazolin-4-amine moiety to replace the adenine group. We identified several compounds with comparable activity to previously reported inhibitors and exhibited selective mTORC1 inhibition and anti-cancer activity. This study further supports the hypothesis that LRS is a promising target to modulate the mTORC1 pathway. 相似文献
8.
Kristopher E. Boyle Dale L. Boger Andrew Wroe Marcelo Vazquez 《Bioorganic & medicinal chemistry letters》2018,28(16):2688-2692
New treatment modalities for glioblastoma multiforme (GBM) are urgently needed. Proton therapy is considered one of the most effective forms of radiation therapy for GBM. DNA alkylating agents such as temozolomide (TMZ) are known to increase the radiosensitivity of GBM to photon radiation. TMZ is a fairly impotent agent, while duocarmycin SA (DSA) is an extremely potent cytotoxic agent capable of inducing a sequence-selective alkylation of duplex DNA. Here, the effects of sub-nM concentrations of DSA on the radiosensitivity of a human GBM cell line (U-138) to proton irradiation were examined. Radiation sensitivity was determined by viability, apoptosis, necrosis and clonogenic assays. DSA concentrations as low as 0.001?nM significantly sensitized U-138 cells to proton irradiation. DSA demonstrates synergistic cytotoxicity against GBM cells treated with proton radiation in vitro, which may represent a novel therapeutic alternative for the treatment of GBM. 相似文献
9.
Ying Wang Bum Han Ryu Wanki Yoo Chang Woo Lee Kyeong Kyu Kim Jun Hyuck Lee T. Doohun Kim 《Biochimica et Biophysica Acta (BBA)/General Subjects》2018,1862(1):197-210
Lactic acid bacteria, which are involved in the fermentation of vegetables, meats, and dairy products, are widely used for the productions of small organic molecules and bioactive peptides. Here, a novel acetylesterase (LaAcE) from Lactobacillus acidophilus NCFM was identified, functionally characterized, immobilized, and subjected to site-directed mutagenesis for biotechnological applications. The enzymatic properties of LaAcE were investigated using biochemical and biophysical methods including native polyacrylamide gel electrophoresis, acetic acid release, biochemical assays, enzyme kinetics, and spectroscopic methods. Interestingly, LaAcE exhibited the ability to act on a broad range of substrates including glucose pentaacetate, glyceryl tributyrate, fish oil, and fermentation-related compounds. Furthermore, immobilization of LaAcE showed good recycling ability and high thermal stability compared with free LaAcE. A structural model of LaAcE was used to guide mutational analysis of hydrophobic substrate-binding region, which was composed of Leu156, Phe164, and Val204. Five mutants (L156A, F164A, V204A, L156A/F164A, and L156A/V204A) were generated and investigated to elucidate the roles of these hydrophobic residues in substrate specificity. This work provided valuable insights into the properties of LaAcE, and demonstrated that LaAcE could be used as a model enzyme of acetylesterase in lactic acid bacteria, making LaAcE a great candidate for industrial applications. 相似文献
10.
To discover new, potent, and selective inhibitors for the murine gamma-aminobutyric acid transporter 4 (mGAT4), the structure-activity relationship (SAR) study of a new cis-alkene analog family based on DDPM-1457 [(S)-2], which previously showed promising inhibitory potency at and subtype selectivity for mGAT4, was conducted. To uncover the importance of the differences between the trans- and the cis-alkene moiety in the spacer, the present publication describes the synthesis of the new compounds via catalytic hydrogenation with Lindlar’s catalyst. The biological results collected by the SAR study revealed that analog rac-7j characterized by a four-instead of a three-carbon atom spacer with a cis double bond applying to the majority of the studied compounds displays a surprisingly high potency at mGAT1 (pIC50?=?6.00?±?0.04) and at the same time a reasonable potency at mGAT4 (pIC50?=?4.82). 相似文献
11.
Ziyi Cai Amanda C. Hahn Weiqing Zhang Iris J. Holzleitner Anthony J. Lee Lisa M. DeBruine Benedict C. Jones 《Evolution and human behavior》2019,40(2):156-159
Previous reports that women with attractive faces are healthier have been widely cited as evidence that sexual selection has shaped human mate preferences. However, evidence for correlations between women's physical health and facial attractiveness is equivocal. Moreover, positive results on this issue have generally come from studies of self-reported health in small samples. The current study took standardized face photographs of women who completed four different health questionnaires assessing susceptibility to infectious illnesses (N?=?590). Of these women, 221 also provided a saliva sample that was assayed for immunoglobulin A (a marker of immune function). Analyses showed no significant correlations between rated facial attractiveness and either scores on any of the health questionnaires or salivary immunoglobulin A. Furthermore there was no compelling evidence that objective measures of sexual dimorphism of face shape, averageness of face shape, or facial coloration were correlated with any of our health measures. While other measures of health may yet reveal robust associations with facial appearance, these null results do not support the prominent and influential assumption that women's facial attractiveness is a cue of young adult women's susceptibility to infectious illnesses, at least in our study population. 相似文献
12.
Jeffrey T. Kuethe Kallol Basu Robert K. Orr Eric Ashley Marc Poirier Lushi Tan 《Bioorganic & medicinal chemistry》2018,26(4):938-944
The evolution of a scalable process for the preparation of methylcyclobutanol-pyridyl ether 1 is described. Key aspects of this development including careful control of the stereochemistry, elimination of chromatography, and application to kilogram-scale synthesis are addressed. 相似文献
13.
Yosuke Nishigaya Kentaro Umei Yoshifumi Saito Hiroyuki Watanabe Tatsuhiro Kondo Atsushi Kondo Naohiro Kawamura Kazuya Tatani Yasushi Kohno Nobuyuki Tanaka Shigeki Seto 《Bioorganic & medicinal chemistry letters》2017,27(17):4044-4050
A scaffold-hopping strategy towards a new pyrazolo[1,5-a]pyridine based core using molecular hybridization of two structurally distinct EP1 antagonists, followed by structure-activity relationship-guided optimization, resulted in the identification of potent EP1 antagonists exemplified by 4c, 4f, and 4j, which were shown to reduce pathological intravesical pressure in rats when administered at 1 mg/kg iv. 相似文献
14.
The pyrolytic behavior of inulin, a (2 → 1)-linked fructofuranan, is described. Parallel investigations of the pyrolysis of glucose and of fructose were conducted to supplement the inulin results and to aid comparison with previous results from glucans. Effects of neutral and basic additives are emphasized. As with glucans, the addition of such additives (especially basic) increases the yields of the one-, two-, and three-carbon products (as well as of hexosaccharinolactones), while generally decreasing the yields of anhydro sugar and furan derivatives. The former products include glycoaldehyde, acetol, dihydroxyacetone, acetic acid, formic acid, and lactic acid. Mechanistic speculations are made regarding the origins of these compounds, as well as of furan derivatives and saccharinic acid lactones. Parallels with alkaline degradation are considered. 相似文献
15.
16.
17.
Mathilde Ménard Florent Meyer Ksenia Parkhomenko Cédric Leuvrey Grégory Francius Sylvie Bégin-Colin Damien Mertz 《Biochimica et Biophysica Acta (BBA)/General Subjects》2019,1863(2):332-341
Human serum albumin (HSA) nanoparticles emerge as promising carriers for drug delivery. Among challenges, one important issue is the design of HSA nanoparticles with a low mean size of ca. 50?nm and having a high drug payload. The original strategy developed here is to use sacrificial mesoporous nanosilica templates having a diameter close to 30?nm to drive the protein nanocapsule formation. This new approach ensures first an efficient high drug loading (ca. 30%) of Doxorubicin (DOX) in the porous silica by functionalizing silica with an aminosiloxane layer and then allows the one-step adsorption and the physical cross-linking of HSA by modifying the silica surface with isobutyramide (IBAM) groups. After silica template removal, homogenous DOX-loaded HSA nanocapsules (30–60?nm size) with high drug loading capacity (ca. 88%) are thus formed. Such nanocapsules are shown efficient in multicellular tumor spheroid models (MCTS) of human hepatocarcinoma cells by their significant growth inhibition with respect to controls. Such a new synthesis approach paves the way toward new protein based nanocarriers for drug delivery. 相似文献
18.
19.
Keisuke Motoyama Tsutomu Nagata Jun Kobayashi Akifumi Nakamura Naoki Miyoshi Miho Kazui Ken Sakurai Tomoko Sakakura 《Bioorganic & medicinal chemistry letters》2018,28(12):2222-2227
In this study, we aimed to synthesize a novel blocker of transient receptor potential canonical 6 (TRPC6). The sp2 carbon atoms of the aminoindane skeleton of the known inhibitor were replaced with sp3 carbon atoms to increase the molecular complexity, measured by fraction sp3 (Fsp3). The representative compound, a bicyclo[4.3.0]nonane derivative DS88790512, inhibited TRPC6 with an IC50 value of 11?nM. Notably, DS88790512 exhibited excellent selectivity against hERG and hNaV1.5 channels, and was identified as an orally bioavailable compound. 相似文献
20.
M.D. Marrodán M. González-Montero de Espinosa Á. Herráez E.L. Alfaro I.F. Bejarano M. Carmenate D.B. Lomaglio N. López-Ejeda A. Martínez M.S. Mesa B. Méndez Pérez J.M. Meléndez S. Moreno-Romero J.L. Pacheco V. Vázquez J.E. Dipierri 《HOMO》2017,68(2):145-155
Subcutaneous fat skinfolds represent a reliable assessment instrument of adiposity status. This study provides current percentile references for four subcutaneous skinfolds (biceps, triceps, subscapular, suprailiac) applicable to children and adolescents in Spain and in Latin American countries where data are scarce.The design consisted of a cross-sectional multicenter study performed with identical methods in 5 countries (Argentina, Cuba, Mexico, Spain and Venezuela). Total sample comprised 9163 children and youths (boys 4615 - girls 4548) aged 6–18 years, healthy and without apparent pathologies. Percentiles 3, 5, 10, 25, 50, 75, 90, 95 and 97 were calculated by the LMS method. Sexual dimorphism was assessed using the t-test and age differences with ANOVA. Normalized growth percentile references were obtained according to sex and age for each skinfold. The mean values of four skinfolds were significantly greater in girls than boys (p < 0.001) and, in both sexes, all skinfolds show statistical differences through age (p < 0.001) with different magnitudes.Except triceps in girls, peaks between 11 and 12 years of age are more noticeable in boys than in girls. Although the general model of growth is known, the skinfold measurements show variability among populations and differences of magnitude are presented according to the analyzed population. Therefore, these age and sex-specific reference percentile values for biceps, triceps, subscapular and suprailiac skinfolds, derived from a large sample of Spanish and Latin American children and adolescents, are a useful tool for adiposity diagnosis in this population for which no reference values were available. 相似文献