- Spermine Derivatives of Indole-3-carboxylic Acid, Indole-3-acetic Acid and Indole-3-acrylic Acid as Gram-Negative Antibiotic Adjuvants
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The discovery of new antibiotic adjuvants is an attractive option for overcoming antimicrobial resistance. We have previously reported the discovery of a bis-6-bromoindolglyoxylamide derivative of spermine as being able to enhance the action of antibiotics against Gram-negative bacteria but suffers from being cytotoxic and red-blood cell haemolytic. A series of analogues was prepared exploring variation of the indolglyoxylamide unit, to include indole-3-acrylic, indole-3-acetic and indole-3-carboxylate units, and evaluated for antibiotic enhancing properties against a range of Gram-negative bacteria, and for intrinsic antimicrobial, cytotoxic and haemolytic properties. Two spermine derivatives, bearing 5-bromo-indole-3-acetic acid (17) and 5-methoxy-indole-3-acrylic acid (14) end groups were found to exhibit good to moderate antibiotic adjuvant activities for doxycycline towards the Gram-negative bacteria Pseudomonas aeruginosa, Escherichia coli and Klebsiella pneumoniae, but with more modest intrinsic antimicrobial activity and greatly reduced cytotoxic and haemolytic properties. The mechanism of action of the latter derivative identified its ability to disrupt the outer membranes of bacteria and to inhibit the AcrAB-TolC efflux pump directly or by inhibiting the proton gradient.
- Cadelis, Melissa M.,Li, Steven A.,Bourguet-Kondracki, Marie-Lise,Blanchet, Marine,Douafer, Hana,Brunel, Jean Michel,Copp, Brent R.
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p. 513 - 523
(2020/11/02)
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- Induction of Apoptosis in Hepatocellular Carcinoma Cell Lines by Novel Indolylacrylamide Derivatives: Synthesis and Biological Evaluation
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Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer and one of the leading causes of cancer associated death worldwide. This is due to the highly resistant nature of this malignancy and the lack of effective treatment options for advanced stage HCC patients. The hyperactivity of PI3K/Akt and Ras/Raf/MEK/ERK signaling pathways contribute to the cancer progression, survival, motility, and resistance mechanisms, and the interaction of these two pathways are responsible for the regulation of cancer cell growth and development. Therefore, it is vital to design and develop novel therapeutic options for HCC treatment targeting these hyperactive pathways. For this purpose, novel series of trans-indole-3-ylacrylamide derivatives originated from the lead compound, 3-(1H-indole-3-yl)-N-(3,4,5-trimethoxyphenyl)acrylamide, have been synthesized and analyzed for their bioactivity on cancer cells along with the lead compound. Based on the initial screening, the most potent compounds were selected to elucidate their effects on cellular signaling activity of HCC cell lines. Cell cycle analysis, immunofluorescence, and Western blot analysis revealed that lead compound and (E)-N-(4-tert-butylphenyl)-3-(1H-indole-3-yl)acrylamide induced cell cycle arrest at the G2/M phase, enhanced chromatin condensation and PARP-cleavage, addressing induction of apoptotic cell death. Additionally, these compounds decreased the activity of ERK signaling pathway, where phosphorylated ERK1/2 and c-Jun protein levels diminished significantly. Relevant to these findings, the lead compound was able to inhibit tubulin polymerization as well. To conclude, the novel trans-indole-3-ylacrylamide derivatives inhibit one of the critical pathways associated with HCC which results in cell cycle arrest and apoptosis in HCC cell lines.
- Hawash, Mohammed,Kahraman, Deniz Cansen,Cetin-Atalay, Rengul,Baytas, Sultan Nacak
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- Synthesis, biological evaluation and molecular docking studies of trans-indole-3-acrylamide derivatives, a new class of tubulin polymerization inhibitors
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In this study, we synthesized a series of trans-indole-3-acrylamide derivatives (3a-k) and investigated their activity for inhibition of cell proliferation against five human cancer cell lines (HeLa, MCF7, MDA-MB-231, Raji and HL-60) by MTT assay. Compound 3e showed significant antiproliferative activity against both the Raji and HL-60 cell lines with IC50 values of 9.5 and 5.1 μM, respectively. Compound 3e also exhibited moderate inhibitory activity on tubulin polymerization (IC50 = 17 μM). Flow cytometric analysis of cultured cells treated with 3e also demonstrated that the compound caused cell cycle arrest at the G2/M phase in HL-60 and HeLa cells. Moreover, 3e, the most active compound, caused an apoptotic cell death through the activation of caspase-3. Docking simulations suggested that 3e binds to the colchicine site of tubulin.
- Baytas, Sultan Nacak,Inceler, Nazan,Yilmaz, Akin,Olgac, Abdurrahman,Menevse, Sevda,Banoglu, Erden,Hamel, Ernest,Bortolozzi, Roberta,Viola, Giampietro
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p. 3096 - 3104
(2014/06/09)
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- Discovery of novel 4-anilinoquinazoline derivatives as potent inhibitors of epidermal growth factor receptor with antitumor activity
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Two new series of new compounds containing a 6-amino-substituted group or 6-acrylamide-substituted group linked to a 4-anilinoquinazoline nucleus have been discovered as potential EGFR inhibitors. These compounds proved efficient effects on antiproliferative activity and EGFR-TK inhibitory activity. Especially, N6-((5-bromothiophen-2-yl)methyl)-N4-(3- chlorophenyl)quinazoline-4,6-diamine (5e), showed the most potent inhibitory activity (IC50 = 3.11 μM for Hep G2, IC50 = 0.82 μM for A549). The EGFR molecular docking model suggested that the new compound is nicely bound to the region of EGFR, and cell morphology by Hoechst stain experiment suggested that these compounds efficiently induced apoptosis of A549 cells.
- Xu, Yun-Yun,Li, Si-Ning,Yu, Gao-Jian,Hu, Qing-Hua,Li, Huan-Qiu
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p. 6084 - 6091
(2013/09/23)
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- Polymer-assisted solution-phase synthesis under combined ultrasound and microwave irradiation: Preparation of α,β-unsaturated esters and carboxylic acids, key intermediates of novel sigma ligands
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The optimal conditions to prepare α,β-unsaturated methyl esters via Wittig reaction combining polymer-assisted solution-phase synthesis (PASPS) methodology and simultaneous ultrasound and microwave irradiation were established. The effects of temperature, solvent, and irradiation time were discussed. Results clearly indicated the superiority of combined ultrasound and microwave-assisted procedure over microwave-assisted methodology. Moreover, an efficient PASPS procedure to prepare α,β-unsaturated carboxylic acids via tandem Wittig olefination and hydrolysis reaction was developed under combined ultrasound and microwave irradiation. Generally, a good conversion of aldehydes to acids was observed. The optimized protocols allowed us to quickly prepare a small collection of either α,β-unsaturated esters or carboxylic acids, key intermediates for the drug-discovery process of new sigma ligands. Copyright Taylor & Francis Group, LLC.
- Rossi,Urbano,Baraglia, A. Carnevale,Serra,Bergamelli,Iannelli,Azzolina,Collina
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experimental part
p. 3254 - 3262
(2011/03/18)
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- Photoinduced, family-specific, site-selective cleavage of TIM-barrel proteins
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(Chemical Equation Presented) Nonenzymatic, chemical methods for the controlled cleavage of proteins at predictable sites in a site-specific manner are rare and of strong potential utility in clean, post-translational manipulation of protein structure for
- Floyd, Nicola,Oldham, Neil J.,Eyles, Christopher J.,Taylor, Stephen,Filatov, Dmitry A.,Brouard, Mark,Davis, Benjamin G.
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supporting information; experimental part
p. 12518 - 12519
(2010/01/29)
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- L-Tryptophan 2',3'-oxidase from Chromobacterium violaceum catalyzes the synthesis of &α,&β-dehydrotryptophanyl residues in peptides and proteins: A tool for chemical modification and labelling of peptides and proteins
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In 1975, Davis et al. reported the capacity of Chromobacterium violaceum (ATCC 12472) to transform Cbz-L-tryptophan into its α,β-dehydro derivative.However, reaction specificity and structural features of the putative enzyme which is responsible for this activity were not determined.We have isolated from this strain an enzyme designated L-tryptophan 2',3'-oxidase, which catalyzes the formation of a double bond at the Cα-Cβ position of tryptophan residues.Using a variety of tryptophan derivatives, we have demonstrated thatthe enzyme is highly specific for unsubstituted indole containing compounds and showed that the enzyme not only acts on isolated tryptophanyl side-chains but is also capable of dehydrogenating tryptophan residues in peptides and proteins.
- Genet, R,Denoyelle, C,Menez, A
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p. 848 - 850
(2007/10/02)
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- Synthesis of Enamides
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(Z)-3-Arylprop-2-enoic acids can be converted by the Curtius procedure, through the acyl azides, into (Z)-2-arylethenyl isocyanates, which with methanol give methyl (Z)-N-(2-arylethenyl)carbamates.Acylation of the (Z)-enecarbamates, through their anions, leads to methyl (Z)-N-acyl-N-(2-arylethenyl)carbamates, which on treatment with lithium iodide in boiling N,N-dimethylformamide or acetonitrile undergo demethoxycarbonylation to give (Z)-enamides.The stereospecific route to enamides can also be used in the E-series.Treatment of (Z)- or (E)-2-arylethenyl isocyanates with trifluoroacetic acid gives (E)-N-(2-arylethenyl)trifluoroacetamides,the anions of which, with acylating agents, give (E)-enamides directly.
- Brettle, Roger,Mosedale, Alan J.
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p. 2185 - 2196
(2007/10/02)
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- Alkenylation of 1-Acylindoles with Olefins Bearing Electron-withdrawing Substituents and Palladium Acetate
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The oxidation of 1-(2,6-dichlorobenzoyl)indole with olefins, such as alkyl acrylates and acrylonitrile, and palladium acetate resulted in selective 3-alkenylation of the indole nucleus.Treatment of 1-acyl-3-methylindoles under similar conditions gave the corresponding 2-alkenyl substituted indoles, while the oxidation of 6-oxo-6H-isoindoloindole gave the corresponding 3-alkenyl substituted indoles.
- Itahara, Toshio,Ikeda, Mizue,Sakakibara, Tsutomu
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p. 1361 - 1363
(2007/10/02)
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