共查询到20条相似文献,搜索用时 46 毫秒
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Dr. Elena V. Moroz-Omori Dr. Danzhi Huang Rajiv Kumar Bedi Sherry J. Cheriyamkunnel Elena Bochenkova Dr. Aymeric Dolbois Maciej D. Rzeczkowski Dr. Yaozong Li Dr. Lars Wiedmer Prof. Amedeo Caflisch 《ChemMedChem》2021,16(19):3035-3043
The methylase METTL3 is the writer enzyme of the N6-methyladenosine (m6A) modification of RNA. Using a structure-based drug discovery approach, we identified a METTL3 inhibitor with potency in a biochemical assay of 280 nM, while its enantiomer is 100 times less active. We observed a dose-dependent reduction in the m6A methylation level of mRNA in several cell lines treated with the inhibitor already after 16 h of treatment, which lasted for at least 6 days. Importantly, the prolonged incubation (up to 6 days) with the METTL3 inhibitor did not alter levels of other RNA modifications (i. e., m1A, m6Am, m7G), suggesting selectivity of the developed compound towards other RNA methyltransferases. 相似文献
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Curcumin Attenuates Lipopolysaccharide‐Induced Hepatic Lipid Metabolism Disorder by Modification of m6A RNA Methylation in Piglets 下载免费PDF全文
Na Lu Xingmei Li Jiayao Yu Yi Li Chao Wang Lili Zhang Tian Wang Xiang Zhong 《Lipids》2018,53(1):53-63
N6‐methyladenosine (m6A) regulates gene expression and affects cellular metabolism. In this study, we checked whether the regulation of lipid metabolism by curcumin is associated with m6A RNA methylation. We investigated the effects of dietary curcumin supplementation on lipopolysaccharide (LPS)‐induced liver injury and lipid metabolism disorder, and on m6A RNA methylation in weaned piglets. A total of 24 Duroc × Large White × Landrace piglets were randomly assigned to control, LPS, and CurL (LPS challenge and 200 mg/kg dietary curcumin) groups (n = 8/group). The results showed that curcumin reduced the increase in relative liver weight as well as the concentrations of aspartate aminotransferase and lactate dehydrogenase induced by LPS injection in the plasma and liver of weaning piglets (p < 0.05). The amounts of total cholesterol and triacylglycerols were decreased by curcumin compared to that by the LPS injection (p < 0.05). Additionally, curcumin reduced the expression of Bcl‐2 and Bax mRNA, whereas it increased the p53 mRNA level in the liver (p < 0.05). Curcumin inhibited the enhancement of SREBP‐1c and SCD‐1 mRNA levels induced by LPS in the liver. Notably, dietary curcumin affected the expression of METTL3, METTL14, ALKBH5, FTO, and YTHDF2 mRNA, and increased the abundance of m6A in the liver of piglets. In conclusion, the protective effect of curcumin in LPS‐induced liver injury and hepatic lipid metabolism disruption might be due to the increase in m6A RNA methylation. Our study provides mechanistic insights into the effect of curcumin in protecting against hepatic injury during inflammation and metabolic diseases. 相似文献
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Inhibition of cholesterol synthesis by cyclopropylamine derivatives of squalene in human hepatoblastoma cells in culture 总被引:1,自引:1,他引:0
W. A. Van Sickle M. R. Angelastro P. Wilson J. R. Cooper A. Marquart M. A. Flanagan 《Lipids》1992,27(3):157-160
Two squalene derivatives, trisnorsqualene cyclopropylamine and trisnorsqualeneN-methylcyclopropylamine, were synthesized and tested for inhibition of lanosterol and squalene epoxide formation from squalene
in rat hepatic microsomes, and for the inhibition of cholesterol syntheses in human cultured hepatoblastoma (HepG2) cells.
Trisnorsqualene cyclopropylamine inhibited [3H]-squalene conversion to [3H]squalene epoxide in microsomes (IC50=5.0 μM), indicating that this derivative inhibited squalene mono-oxygenase. Trisnorsqualenen-methylcyclopropylamine inhibited [3H]squalene conversion to [3H]lanosterol (IC50=12.0 μM) and caused [3H]-squalene epoxide to accumulate in microsomes, indicating that this derivative inhibited 2,3-oxidosqualene cyclase. Cholesterol
biosynthesis from [14C]acetate in HepG2 cells was inhibited by both derivatives (IC50=1.0 μM for trisnorsqualene cyclopropylamine; IC50=0.5 μM for trisnorsqualeneN-methylcyclopropylamine). Cells incubated with trisnorsqualene cyclopropylamine accumulated [14C]squalene, while cells incubated with trisnorsqualeneN-methylcyclopropylamine accumulated [14C]squalene epoxide and [14C]squalene diepoxide. The concentration range of inhibitor which caused these intermediates to accumulate coincided with that
which inhibited cholesterol synthesis. The results indicate that cyclopropylamine derivatives of squalene are effective inhibitors
of cholesterol synthesis, and that substitutions at the nitrogen affect enzyme selectivity and thus the mechanism of action
of the compounds. 相似文献
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Yu‐Ting Huang Syue‐Yi Lyu Pei‐Hsuan Chuang Ning‐Shian Hsu Yi‐Shan Li Hsiu‐Chien Chan Chuen‐Jiuan Huang Yu‐Chen Liu Chang‐Jer Wu Dr. Wen‐Bin Yang Dr. Tsung‐Lin Li Dr. 《Chembiochem : a European journal of chemical biology》2009,10(15):2480-2487
Mannopeptimycin, a potent drug lead, has superior activity against difficult‐to‐treat multidrug‐resistant Gram‐positive pathogens such as methicillin‐resistant Staphylococcus aureus (MRSA). (2S,3S)‐β‐Methylphenylalanine is a residue in the cyclic hexapeptide core of mannopeptimycin, but the synthesis of this residue is far from clear. We report here on the reaction order and the stereochemical course of reaction in the formation of (2S,3S)‐β‐methylphenylalanine. The reaction is executed by the enzymes MppJ and TyrB, an S‐adenosyl methionine (SAM)‐dependent methyltransferase and an (S)‐aromatic‐amino‐acid aminotransferase, respectively. Phenylpyruvic acid is methylated by MppJ at its benzylic position at the expense of one equivalent of SAM. The resulting β‐methyl phenylpyruvic acid is then converted to (2S,3S)‐β‐methylphenylalanine by TyrB. MppJ was further determined to be regioselective and stereoselective in its catalysis of the formation of (3S)‐β‐methylphenylpyruvic acid. The binding constant (KD) of MppJ versus SAM is 26 μM . The kinetic constants with respect to kcat Ppy and KM Ppy, and kcat SAM and KM SAM are 0.8 s?1 and 2.5 mM , and 8.15 s?1 and 0.014 mM , respectively. These results suggest SAM has higher binding affinity for MppJ than Ppy, and the C? C bond formation in βmPpy might be the rate‐limiting step, as opposed to the C? S bond breakage in SAM. 相似文献
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Two lines of evidence led us to reexamine the possibility that methylation of phosphoethanolamine and its partially methylated
derivatives, in addition to methylation of the corresponding phosphatidyl derivatives, plays a role in mammalian phosphatidylcholine
biosynthesis: (a) Results obtained by Salerno and Beeler with rat [Salerno, D. M. and Beeler, D. A. (1973)Biochim. Biophys. Acta 326, 325–338] appear to strongly support such a role for methylation of phosphobases; (b) Such reactions have recently been shown
to play major roles in phosphatidylcholine synthesis by higher plants [see Datko, A. H. and Mudd, S. H. (1988)Plant Physiol. 88, 854–861 and references therein]. We found that, following coninuous labeling of rat liver with L-[methyl-3H]methionine for 10.4 min (intraperitoneal administration) or for 0.75 min (intraportal administration), virtually no3H was detected in methylated derivatives of phosphoethanolamine, but readily detectable amounts of3H were present in the base moiety of each methylated derivative of phosphatidylethanolamine. Thus, there was no indication
that phospho-base methylation makes a significant contribution. Studies of cultured rat hepatoma cells showed definitively
for the first time in a mammalian system that choline deprivation up-regulates the rate of flow of methyl groups originating
in methionine into phosphatidylethanolamine and derivatives. Even under these conditions, methylation of phosphoethanolamine
bases appeared to play a negligible role. 相似文献
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Dr. Giulio Ferino Prof. Enzo Cadoni Dr. Maria João Matos Dr. Elias Quezada Prof. Eugenio Uriarte Prof. Lourdes Santana Dr. Santiago Vilar Dr. Nicholas P. Tatonetti Matilde Yáñez Dolores Viña Dr. Carmen Picciau Dr. Silvia Serra Prof. Giovanna Delogu 《ChemMedChem》2013,8(6):956-966
Monoamine oxidase (MAO) is an important drug target for the treatment of neurological disorders. Several 3‐arylcoumarin derivatives were previously described as interesting selective MAO‐B inhibitors. Preserving the trans‐stilbene structure, a series of 2‐arylbenzofuran and corresponding 3‐arylcoumarin derivatives were synthesized and evaluated as inhibitors of both MAO isoforms, MAO‐A and MAO‐B. In general, both types of derivatives were found to be selective MAO‐B inhibitors, with IC50 values in the nano‐ to micromolar range. 5‐Nitro‐2‐(4‐methoxyphenyl)benzofuran ( 8 ) is the most active compound of the benzofuran series, presenting MAO‐B selectivity and reversible inhibition (IC50=140 nM ). 3‐(4′‐Methoxyphenyl)‐6‐nitrocoumarin ( 15 ), with the same substitution pattern as that of compound 8 , was found to be the most active MAO‐B inhibitor of the coumarin series (IC50=3 nM ). However, 3‐phenylcoumarin 14 showed activity in the same range (IC50=6 nM ), is reversible, and also severalfold more selective than compound 15 . Docking experiments for the most active compounds into the MAO‐B and MAO‐A binding pockets highlighted different interactions between the derivative classes (2‐arylbenzofurans and 3‐arylcoumarins), and provided new information about the enzyme–inhibitor interaction and the potential therapeutic application of these scaffolds. 相似文献
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A Tandem Enzymatic sp2‐C‐Methylation Process: Coupling in Situ S‐Adenosyl‐l‐Methionine Formation with Methyl Transfer 下载免费PDF全文
Joanna C. Sadler Dr. Luke D. Humphreys Radka Snajdrova Dr. Glenn A. Burley 《Chembiochem : a European journal of chemical biology》2017,18(11):992-995
A one‐pot, two‐step biocatalytic platform for the regiospecfic C‐methylation and C‐ethylation of aromatic substrates is described. The tandem process utilises SalL (Salinospora tropica) for in situ synthesis of S‐adenosyl‐l ‐methionine (SAM), followed by alkylation of aromatic substrates by the C‐methyltransferase NovO (Streptomyces spheroides). The application of this methodology is demonstrated for the regiospecific labelling of aromatic substrates by the transfer of methyl, ethyl and isotopically labelled 13CH3, 13CD3 and CD3 groups from their corresponding SAM analogues formed in situ. 相似文献
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The local deposition of Ag nanoparticles (NPs) on ω-mercaptoalkanoic acid, HS(CH2)nCO2H, (n = 2, 10) self-assembled monolayers (SAMs) by scanning electrochemical microscopy (SECM) is reported. We found that the presence of a SAM had a pronounced effect on Ag deposition. Experiments were conducted by applying different potentials to an Au(1 1 1) substrate either in the presence of a constant concentration of Ag+ ions in solution (bulk deposition) or by generating a flux of Ag+ from an Ag microelectrode that was positioned close to the Au(1 1 1) substrate (SECM deposition). SECM was used for generating a controlled flux of silver ions by anodic dissolution of an Ag microelectrode close to the SAMs modified Au(1 1 1). We found that the shape of the NPs was affected by the length of the carbon-chain of the SAM. Tetrahedral NPs were obtained on bare Au(1 1 1) surfaces while rod like and cubic Ag NPs were deposited onto 3-mercaptopropanoic acid (MPA) and 11-mercaptoundecanoic acid (MUA) SAMs, respectively. The size and shape of the deposited NPs were influenced by the deposition potential.We conclude that the shape and distribution of locally deposited Ag NPs on Au(1 1 1) can be controlled by modification of the substrate with a SAM and through controlling the Ag+ flux generated by SECM. 相似文献
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Dr. Rayane Ghoteimi Dr. Abdennour Braka Céline Rodriguez Emeline Cros-Perrial Dr. Valentin Duvauchelle Dr. Jean-Pierre Uttaro Prof. Dr. Christophe Mathé Dr. Christine Ménétrier-Caux Dr. Lars Petter Jordheim Dr. Laurent Chaloin Dr. Suzanne Peyrottes 《ChemMedChem》2023,18(7):e202200594
Various series of 4,6-biaryl-2-thiopyridine derivatives were synthesized and evaluated as potential ecto-5′-nucleotidase (CD73) inhibitors. Two synthetic routes were explored and the coupling of 4,6-disubstituted 3-cyano-2-chloro-pyridines with selected thiols allowed us to explore the structural diversity. Somehow divergent results were obtained in biological assays on CD73 inhibition using either the purified recombinant protein or cell-based assays, highlighting the difficulty to target protein-protein interface on proteins existing as soluble and membrane-bound forms. Among the 18 new derivatives obtained, three derivatives incorporating morpholino substituents on the 4,6-biaryl-2-thiopyridine core were shown to be able to reverse the adenosine-mediated immune suppression on human T cells. The higher blockade efficiency was observed for 2-((3-cyano-4,6-bis(4-morpholinophenyl)pyridin-2-yl)thio)-N-(isoxazol-3-yl)acetamide (with total reversion at 100 μM) and methyl 2-((3-cyano-4,6-bis(4-morpholinophenyl)pyridin-2-yl)thio)acetate (with partial reversion at 10 μM). Thus, this series of compounds illustrates a new chemotype of CD73 allosteric inhibitors. 相似文献
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Minghua Li Xiumei Meng Enjie Diao Fangling Du Xiaoyan Zhao 《Journal of chemical technology and biotechnology (Oxford, Oxfordshire : 1986)》2012,87(10):1379-1384
BACKGROUND: Saccharomyces cerevisiae is one of the main microorganisms that can produce S‐adenosylmethionine (SAM) from L‐methionine and ATP with high productivity. To satisfy the ATP requirement for SAM synthesis, sufficient oxygen should be supplied to the medium to improve aerobic metabolism in S. cerevisiae. In this study, n‐hexadecane used as oxygen vector for enhancement of SAM production by this yeast was investigated. RESULTS: N‐hexadecane was most favorable for cell growth and SAM synthesis in S. cerevisiae when added at the time of inoculation. It could increase glucose consumption, reduce ethanol accumulation, and ultimately improve biomass and SAM productivity in a fermentation process. In a bioreactor, the highest yield of SAM (2.27 g L?1) was achieved in the presence of 4% (v/v) n‐hexadecane after 24 h of inoculation, which was 23.37% higher than the control (1.84 g L?1). CONCLUSION: The addition of n‐hexadecane to cultures of S. cerevisiae significantly enhanced SAM production without increasing energy consumption, and has the potential for use in large‐scale fermentation processes to increase oxygen supply. Copyright © 2012 Society of Chemical Industry 相似文献
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Six apigenin derivatives were synthesized through Mannich reaction by using apigenin isolated from Hypericum perforatum as raw material. The inhibition performance of these apigenin derivatives were investigated as eco-friendly corrosion inhibitors for brass in 1.0 M HNO3 solution by means of weight loss, potentiodynamic polarization, and electrochemical impedance spectroscopy (EIS) measurements. The obtained results show that the as-synthesized apigenin derivatives act as efficient inhibitors for brass in 1.0 M HNO3. The inhibition efficiency increased with the increase in inhibitor concentration but decreased with a rise in temperature. The inhibition efficiency higher than 90% for these compounds was found even at a low concentration of 30?mg L?1, which is superior to the commonly used synthetic organic corrosion inhibitors for brass in acidic media. Electrochemical studies indicate that the inhibitors are of mixed type but predominantly cathodic in HNO3 solution. The inhibitor performance depends on the adsorption of the molecules on the metal surface. The thermodynamic parameters for inhibiting process were calculated according to the statistical model. The calculated thermodynamic parameters revealed that the adsorption of these inhibitors on brass surface was spontaneous, controlled by physiochemical processes. The adsorption behaviour of these apigenin derivatives on the surface of brass was analyzed utilizing SEM, AFM, XPS, and Raman spectroscopy measurements. The results confirmed that the apigenin derivatives prevented corrosion of brass by forming protective layer on its surface. 相似文献
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Emma Langella Dr. Sébastien Pierre Dr. Wadih Ghattas Dr. Michel Giorgi Dr. Marius Réglier Dr. Michele Saviano Dr. Luciana Esposito Dr. Renaud Hardré Dr. 《ChemMedChem》2010,5(9):1568-1576
Specific inhibition of the copper‐containing peptidylglycine α‐hydroxylating monooxygenase (PHM), which catalyzes the post‐translational modification of peptides involved in carcinogenesis and tumor progression, constitutes a new approach for combating cancer. We carried out a structure–activity study of new compounds derived from a well‐known PHM substrate analogue, the olefinic compound 4‐phenyl‐3‐butenoic acid (PBA). We designed, synthesized, and tested various PBA derivatives both in vitro and in silico. We show that it is possible to increase PBA affinity for PHM by appropriate functionalization of its aromatic nucleus. Compound 2 d , for example, bears a meta‐benzyloxy substituent, and exhibits better inhibition features (Ki=3.9 μM , kinact/Ki=427 M ?1 s?1) than the parent PBA (Ki=19 μM , kinact/Ki=82 M ?1 s?1). Docking calculations also suggest two different binding modes for PBA derivatives; these results will aid in the development of further PHM inhibitors with improved features. 相似文献
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Wei-hua Li Qiao He Sheng-tao Zhang Chang-ling Pei Bao-rong Hou 《Journal of Applied Electrochemistry》2008,38(3):289-295
Two triazole derivatives, 3,4-dichloro-acetophenone-O-1′-(1′,3′,4′-triazolyl)-methaneoxime (4-DTM) and 2,5-dichloro-acetophenone-O-1′-(1′,3′,4′-triazolyl)-methaneoxime (5-DTM) were synthesized, and the inhibition effects for mild steel in 1 M HCl solutions
were investigated by weight loss measurements, electrochemical tests and scanning electronic microscopy (SEM). The weight
loss measurements showed that these compounds have excellent inhibiting effect at a concentration of 1.0 × 10−3 M. The potentiodynamic polarization experiment revealed that the triazole derivatives are inhibitors of mixed-type and electrochemical
impedance spectroscopy (EIS) confirmed that changes in the impedance parameters (R
ct and C
dl) are due to surface adsorption. The inhibition efficiencies obtained from weight loss measurements and electrochemical tests
were in good agreement. Adsorption followed the Langmuir isotherm with negative values of the free energy of adsorption
. The thermodynamic parameters of adsorption were determined and are discussed. Results show that both 4-DTM and 5-DTM are
good inhibitors for mild steel in acid media. 相似文献
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Dr. Kai S. Yang Xinyu R. Ma Dr. Yuying Ma Dr. Yugendar R. Alugubelli Danielle A. Scott Erol C. Vatansever Aleksandra K. Drelich Dr. Banumathi Sankaran Zhi Z. Geng Lauren R. Blankenship Hannah E. Ward Yan J. Sheng Jason C. Hsu Kaci C. Kratch Dr. Baoyu Zhao Hamed S. Hayatshahi Jin Liu Prof. Pingwei Li Prof. Carol A. Fierke Prof. Chien-Te K. Tseng Prof. Shiqing Xu Prof. Wenshe Ray Liu 《ChemMedChem》2021,16(6):942-948
The COVID-19 pathogen, SARS-CoV-2, requires its main protease (SC2MPro) to digest two of its translated long polypeptides to form a number of mature proteins that are essential for viral replication and pathogenesis. Inhibition of this vital proteolytic process is effective in preventing the virus from replicating in infected cells and therefore provides a potential COVID-19 treatment option. Guided by previous medicinal chemistry studies about SARS-CoV-1 main protease (SC1MPro), we have designed and synthesized a series of SC2MPro inhibitors that contain β-(S-2-oxopyrrolidin-3-yl)-alaninal (Opal) for the formation of a reversible covalent bond with the SC2MPro active-site cysteine C145. All inhibitors display high potency with Ki values at or below 100 nM. The most potent compound, MPI3, has as a Ki value of 8.3 nM. Crystallographic analyses of SC2MPro bound to seven inhibitors indicated both formation of a covalent bond with C145 and structural rearrangement from the apoenzyme to accommodate the inhibitors. Virus inhibition assays revealed that several inhibitors have high potency in inhibiting the SARS-CoV-2-induced cytopathogenic effect in both Vero E6 and A549/ACE2 cells. Two inhibitors, MPI5 and MPI8, completely prevented the SARS-CoV-2-induced cytopathogenic effect in Vero E6 cells at 2.5–5 μM and A549/ACE2 cells at 0.16–0.31 μM. Their virus inhibition potency is much higher than that of some existing molecules that are under preclinical and clinical investigations for the treatment of COVID-19. Our study indicates that there is a large chemical space that needs to be explored for the development of SC2MPro inhibitors with ultra-high antiviral potency. 相似文献
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Challenges Based on Antiplasmodial and Antiviral Activities of 7-Chloro-4-aminoquinoline Derivatives
Dr. Satoshi Mizuta Dr. Farhana Mosaddeque Dr. Mya Myat Ngwe Tun Dr. Awet Alem Teklemichael Mayumi Taniguchi Masashi Hosokawa Tomoko Yamaguchi Dr. Juliann Makau Dr. Nguyen Tien Huy Dr. Shusaku Mizukami Prof. Noriyuki Nishida Prof. Kouichi Morita Prof. Kenji Hirayama 《ChemMedChem》2023,18(7):e202200586
We report the structural functionalization of the terminal amino group of N1-(7-chloroquinolin-4-yl) butane-1,4-diamine, leading to a series of 7-chloro-4-aminoquinoline derivatives, and their evaluation as potent anti-malarial and anti-viral agents. Some compounds exhibited promising anti-malarial effects against the Plasmodium falciparum 3D7 (chloroquine-sensitive) and Dd2 (chloroquine-resistant) strains. In addition, these compounds were assayed in vitro against influenza A virus (IAV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Compound 5 h , bearing an N-mesityl thiourea group, displayed pronounced anti-infectious effects against malaria, IAV, and SARS-CoV-2. These results provide new insights into drug discovery for the prevention or treatment of malaria and virus co-infection. 相似文献
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Spontaneous adsorption of 1,8,15,22-tetraaminophthalocyanatocobalt(II) (4α-CoIITAPc) on glassy carbon (GC) electrode leads to the formation of a stable self-assembled monolayer (SAM). Since the SAM of 4α-CoIITAPc is redox active, its adsorption on GC electrode was followed by cyclic voltammetry. SAM of 4α-CoIITAPc on GC electrode shows two pairs of well-defined redox peaks corresponding to CoIII/CoII and CoIIIPc−1/CoIIIPc−2. The surface coverage (Γ) value, calculated by integrating the charge under CoII oxidation, was used to study the adsorption thermodynamics and kinetics of 4α-CoIITAPc on GC surface. Cyclic voltammetric studies show that the adsorption of 4α-CoIITAPc on GC electrode has reached the saturation coverage (Γs) within 3 h. The Γs value for the SAM of 4α-CoIITAPc on GC electrode was found to be 2.37 × 10−10 mol cm−2. Gibbs free energy (ΔGads) and adsorption rate constant (kad) for the adsorption of 4α-CoIITAPc on GC surface were found to be −16.76 kJ mol−1 and 7.1 M−1 s−1, respectively. The possible mechanism for the self-assembly of 4α-CoIITAPc on GC surface is through the addition of nucleophilic amines to the olefinic bond on the GC surface in addition to a meager contribution from π stacking. The contribution of π stacking was confirmed from the adsorption of unsubstituted phthalocyanatocobalt(II) (CoPc) on GC electrode. Raman spectra for the SAM of 4α-CoIITAPc on carbon surface shows strong stretching and breathing bands of Pc macrocycle, pyrrole ring and isoindole ring. Raman and CV studies suggest that 4α-CoIITAPc is adopting nearly a flat orientation or little bit tilted orientation. 相似文献
19.
1‐(1H‐Indol‐3‐yl)ethanamine Derivatives as Potent Staphylococcus aureus NorA Efflux Pump Inhibitors 下载免费PDF全文
Dr. Arnaud Hequet Dr. Olga N. Burchak Dr. Matthieu Jeanty Dr. Xavier Guinchard Dr. Emmanuelle Le Pihive Dr. Laure Maigre Pascale Bouhours Prof. Dominique Schneider Prof. Max Maurin Dr. Jean‐Marc Paris Dr. Jean‐Noël Denis Prof. Dr. Claude Jolivalt 《ChemMedChem》2014,9(7):1534-1545
The synthesis of 37 1‐(1H‐indol‐3‐yl)ethanamine derivatives, including 12 new compounds, was achieved through a series of simple and efficient chemical modifications. These indole derivatives displayed modest or no intrinsic anti‐staphylococcal activity. By contrast, several of the compounds restored, in a concentration‐dependent manner, the antibacterial activity of ciprofloxacin against Staphylococcus aureus strains that were resistant to fluoroquinolones due to overexpression of the NorA efflux pump. Structure–activity relationships studies revealed that the indolic aldonitrones halogenated at position 5 of the indole core were the most efficient inhibitors of the S. aureus NorA efflux pump. Among the compounds, (Z)‐N‐benzylidene‐2‐(tert‐butoxycarbonylamino)‐1‐(5‐iodo‐1H‐indol‐3‐yl)ethanamine oxide led to a fourfold decrease of the ciprofloxacin minimum inhibitory concentration against the SA‐1199B strain when used at a concentration of 0.5 mg L ?1. To the best of our knowledge, this activity is the highest reported to date for an indolic NorA inhibitor. In addition, a new antibacterial compound, tert‐butyl (2‐(3‐hydroxyureido)‐2‐(1H‐indol‐3‐yl)ethyl)carbamate, which is not toxic for human cells, was also found. 相似文献
20.
Díaz-Moscoso A Méndez-Ardoy A Ortega-Caballero F Benito JM Ortiz Mellet C Defaye J Robinson TM Yohannes A Karginov VA García Fernández JM 《ChemMedChem》2011,6(1):181-192
Three new series of potential anthrax toxin inhibitors based on the β‐cyclodextrin (βCD) scaffold were developed by exploiting face‐selective CuI‐catalyzed azide–alkyne 1,3‐cycloadditions, amine–isothiocyanate coupling, and allyl group hydroboration–oxidation/hydroxy → amine replacement reactions. The molecular design follows the “symmetry–complementarity” concept between homogeneously functionalized polycationic βCD derivatives and protective antigen (PA), a component of anthrax toxin known to form C7‐symmetric pores on the cell membrane used by lethal and edema factors to gain access to the cytosol. The synthesis and antitoxin activity of a collection of βCD derivatives differing in the number, arrangement, and face location of the cationic elements are reported herein. These results set the basis for a structure–activity relationship development program of new candidates to combat the anthrax threat. 相似文献