- Synthetic modeling of the structure and function of the rare-earth dependent methanol dehydrogenase cofactor
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Historically, rare-earth ions have been considered irrelevant to biology. Recently, the active sites of certain methanol dehydrogenase (MDH) enzymes have been shown to contain a redox-inactive, rare-earth (RE) cation coordinated by the redox-active pyrroloquinoline quinone (PQQ) cofactor. Importantly, it was demonstrated that rare earths were essential for the growth of certain methylotrophs that incorporated the XoxF-MDH. In this chapter, we summarize the optimized synthesis of a previously published rare-earth complex that serves as a model of the active site of this RE-containing MDH enzyme. The structure and reactivity of the metalated complex, [La(LQQ)(NO3)3] are also discussed. [La(LQQ)(NO3)3] catalytically oxidizes the test alcohol substrate, p-methylbenzyl alcohol, 4MeBnOH, to p-methylbenzaldehyde, 4MePhCHO, in the presence of a base (2,6-lutidine) and a terminal oxidant (ferrocenium hexafluorophosphate) with ~ 17 turnovers. By studying this synthetic model, we have developed a body of evidence about both the reactivity and the mechanism of dehydrogenation of alcohols as a molecular analogue to a native, rare-earth dependent enzyme.
- Knasin, Alison L.,Schelter, Eric J.
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- Design, Synthesis, and Structure-Activity Relationship Studies of Novel Indolyalkylpiperazine Derivatives as Selective 5-HT1A Receptor Agonists
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5-HT1A receptor (5-HT1AR) agonists have been implicated in the treatment of a variety of central nervous system (CNS) diseases such as depression and anxiety, et al. Based on our previously found compound FW01 (Ki = 51 ± 16 nM) obtained by virtual screening, a series of FW01 derivatives were designed and synthesized by the modification of the amide tail group as well as indole headgroup of FW01. SAR exploration found that amide tail group and indole headgroup play pivotal roles in determining the binding affinity and selectivity on dopamine and serotonin receptor subtypes. Among all tested compounds, 9_24 has a Ki value of 5 ± 0.6 nM with a good selectivity toward 5-HT1AR. The [35S] GTPγS assay showed that 9_24 is a full agonist toward 5-HT1AR with an EC50 value of 0.059 nM, which shows 266.2 and 146.4-fold selectivity to 5-HT2A and D3 respectively. Molecular dynamics simulations and molecular docking studies with 5-HT1AR-9_24 were performed to disclose the mechanism of its high activity and selectivity. Finally, a detailed stepwise 9_24 induced signal transduction mechanism of 5-HT1AR is proposed.
- Wang, Wenli,Zheng, Lan,Li, Wei,Zhu, Chen,Peng, Weiqing,Han, Bing,Fu, Wei
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p. 235 - 248
(2020/02/18)
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- Palladium-catalyzed olefination of aryl/alkyl halides with trimethylsilyldiazomethane via carbene migratory insertion
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The direct olefination of aryl/alkyl halides with trimethylsilyldiazomethane (TMSD) as a C1- or C2-unit was achieved successfully via a metal carbene migratory insertion process, which offered a new access to afford (E)-vinyl silanes and (E)-silyl-substituted α,β-unsaturated amides in good yields and high chemoselectivity.
- Mu, Qiu-Chao,Wang, Xing-Ben,Ye, Fei,Sun, Yu-Li,Bai, Xing-Feng,Chen, Jing,Xia, Chun-Gu,Xu, Li-Wen
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supporting information
p. 12994 - 12997
(2018/11/23)
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- New Cyclohexylamine-Dithiocarbamate derivatives as potential anti-microbial agents
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In this study, 2-(substituted-sulfanyl)-N,N-dicyclohexylacetamide derivatives (2a-2g) and 2-(dicyclohexylamino)-2-oxoethyl-1-substituted carbodithioate derivatives (2h-2m) were synthesized and screened for their antimicrobial activity. Methods: Newly synthesized compounds were screened against two gram negative bacteria (S. typhimurium and E.coli), three gram positive bacteria (S. aureus, B. cereus and L. monocytogenes), four Candida species, four Aspergillus spp. and three Penicillium spp. Among them (2a-2m), compounds 2i (2-(dicyclohexylamino)-2-oxoethyl-thiomorpholine-4-carbodithioate) and 2k (2-(dicyclohexylamino)-2-oxoethyl-4-(4-methoxyphenyl)piperazine-1-carbodithioate) were detected to have higher inhibitory effect than other compounds. Results and Conclusion: Minumum inhibitor concentrations (MICs) of the compounds were determined between the range of 97.5-390 ìg/mL. Additionally, parameters determined that some physicochemical and toxic properties were predicted using computational methods.
- Yurtta, Leyla,Kaya, Betül,Cankilic, Meral Yilmaz,Levent, Serkan
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p. 1308 - 1315
(2017/11/14)
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- Thioimidazoline based compounds reverse glucocorticoid resistance in human acute lymphoblastic leukemia xenografts
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Glucocorticoids form a critical component of chemotherapy regimens for pediatric acute lymphoblastic leukemia (ALL) and the initial response to glucocorticoid therapy is a major prognostic factor, where resistance is predictive of poor outcome. A high-throughput screen identified four thioimidazoline-containing compounds that reversed dexamethasone resistance in an ALL xenograft derived from a chemoresistant pediatric ALL. The lead compound (1) was synergistic when used in combination with the glucocorticoids, dexamethasone or prednisolone. Synergy was observed in a range of dexamethasone-resistant xenografts representative of B-cell precursor ALL (BCP-ALL) and T-cell ALL. We describe here the synthesis of twenty compounds and biological evaluation of thirty two molecules that explore the structure-activity relationships (SAR) of this novel class of glucocorticoid sensitizing compounds. SAR analysis has identified that the most effective dexamethasone sensitizers contain a thioimidazoline acetamide substructure with a large hydrophobic moiety on the acetamide. This journal is
- Toscan, Cara E.,Rahimi, Marwa,Bhadbhade, Mohan,Pickford, Russell,McAlpine, Shelli R.,Lock, Richard B.
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p. 6299 - 6312
(2015/06/08)
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- In vitro antimalarial activity, β-haematin inhibition and structure-activity relationships in a series of quinoline triazoles
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A novel series of quinoline triazole amide analogues (38-51) has been synthesized. Analogues 38-44 had a Cl substituent at the 7-position of the quinoline ring, while 45-51 had a CN substituent at this position. Compounds 40, 45 and 49 were found to be the most active in the series against the Plasmodium falciparum chloroquine-sensitive D10 strain, with IC50 values in the range of 349-1247 nM, with 40 and 45, but not 49 also exhibiting similar activity against the chloroquine-resistant K1 strain of parasite. Quinoline triazoles 40 and 44 were the most active β-haematin inhibitors, with 50% inhibitory concentrations of 14.7 and 8.9 μM respectively. In vitro antimalarial activity of the 7-Cl bearing analogues 38-44 exhibited a strong linear dependence of log(1/IC50) on log P. Thus, the more lipophilic, the more active it was found be. The 7-CN series 45-51 showed no such dependence. The resistance index (IC50 K1/IC50 D10) also exhibited a linear dependence on log P, with a substantially steeper slope in the case of the 7-Cl series. The findings demonstrate the feasibility of producing hydrophilic analogues with strong activity and low cross-resistance with chloroquine.
- Joshi, Mukesh C.,Wicht, Kathryn J.,Taylor, Dale,Hunter, Roger,Smith, Peter J.,Egan, Timothy J.
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p. 338 - 347
(2013/10/21)
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- Triazoloamides as potent γ-secretase modulators with reduced hERG liability
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Synthesis and SAR studies of novel aryl triazoles as gamma secretase modulators (GSMs) are presented in this communication. Starting from our aryl triazole leads, optimization studies were continued and the series progressed towards novel amides and lactams. Triazole 57 was identified as the most potent analog in this series, displaying single-digit nanomolar Aβ42 IC 50 in cell-based assays and reduced affinity for the hERG channel.
- Fischer, Christian,Zultanski, Susan L.,Zhou, Hua,Methot, Joey L.,Shah, Sanjiv,Nuthall, Hugh,Hughes, Bethany L.,Smotrov, Nadja,Hill, Armetta,Szewczak, Alexander A.,Moxham, Christopher M.,Bays, Nathan,Middleton, Richard E.,Munoz, Benito,Shearman, Mark S.
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scheme or table
p. 3140 - 3146
(2012/06/04)
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- SYNTHESIS AND BINDING STUDIES OF NEUTRAL DIOXYDIAMIDE IONOPHORES III
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The syntheses of several bis-(1,2-phenylenedioxydiacetamides) with eight binding sites (four ethers, four amides) are described.It had been anticipated that these bis-compounds would be much stronger binders for Group IIA cations than are members of our previously described 1,2-phenylenedioxydiacetamide system, e.g. 1-3, which give isolable complexes usually of 2:1 ligand/metal cation stoichiometry.Binding constants for the new diesters 4 and 5 were determined in methanol using UV absorption changes and the Scatchard method.The binding strength of 4 was concentration dependent and only moderately greater than that for 1 or for the more closely related 4-hydroxymethyl compound 3.Diester 5 was a weaker binder for Group IIA cations than was either 1 or 3.Cooperativity of the two sets of binding sites with either Sr2+ or Ba2+ was demonstrated for 4 but not for 5.Electrochemical selectivity values (Kpot ij) as determined by Simon et al for 4, 5 and 6, in liquid membrane electrodes are reported for various cations.High ion selectivity for Na1+ vs either Ca2+ or K+ were found, especially for 6.
- Borowitz, Grace B.,Borowitz, Irving J.,Readio, Josephine D.,Rubinstein, Gabriel,Nirchio, Peter,et al.
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p. 4383 - 4394
(2007/10/02)
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- Evaluation of glycolamide esters and various other esters of aspirin as true aspirin prodrugs
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A series of glycolamide, glycolate, (acyloxy)methyl, alkyl, and aryl esters of acetylsalicylic acid (aspirin) were synthesized and evaluated as potential prodrug forms of aspirin. N,N-Disubstituted glycolamide esters were found to be rapidly hydrolized in human plasma, resulting in the formation of aspirin as well as the corresponding salicylate esters. These in turn hydrolyzed rapidly to salicylic acid. The largest amount of aspirin formed from the esters were 50 and 55% in case of the N,N-dimethyl- and N,N-diethylglycolamide esters, respectively. Similar results were obtained in blood with the N,N-dimethyl- and N,N-diethylglycolamide esters. Unsubstituted and monosubstituted glycolamide esters as well as most other esters previously suggested to be aspirin prodrugs were shown to hydrolyze exclusively to the corresponding salicylic acid esters. Lipophilicity parameters and water solubilities of the esters were determined, and structural factors favoring ester prodrug hydrolysis at the expense of deacetylation to yield salicylate ester are discussed. The properties of some N,N-disubstituted glycolamide esters of aspirin are highlighted with respect to their use as potential aspirin prodrugs.
- Nielsen,Bundgaard
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p. 727 - 734
(2007/10/02)
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