- Triazolopyridinyl-acrylonitrile derivatives as antimicrotubule agents: Synthesis, in vitro and in silico characterization of antiproliferative activity, inhibition of tubulin polymerization and binding thermodynamics
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In this paper we report the synthesis, in vitro anticancer activity, and the experimental/computational characterization of mechanism of action of a new series of E isomers of triazolo[4,5-b/c]pyridin-acrylonitrile derivatives (6c-g, 7d-e, 8d-e, 9c-f, 10d-e, 11d-e). All new compounds are endowed with moderate to interesting antiproliferative activity against 9 different cancer cell lines derived from solid and hematological human tumors. Fluorescence-based assays prove that these molecules interfere with tubulin polymerization. Furthermore, isothermal titration calorimetry (ITC) provides full tubulin/compound binding thermodynamics, thereby ultimately qualifying and quantifying the interactions of these molecular series with the target protein. Lastly, the analysis based on the tight coupling of in vitro and in silico modeling of the interactions between tubulin and the title compounds allows to propose a molecular rationale for their biological activity.
- Briguglio, Irene,Laurini, Erik,Pirisi, Maria Antonietta,Piras, Sandra,Corona, Paola,Fermeglia, Maurizio,Pricl, Sabrina,Carta, Antonio
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- Mild and general access to diverse 1H-benzotriazoles via diboron-mediated N-OH deoxygenation and palladium-catalyzed C-C and C -N bond formation
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Benzotriazoles are a highly important class of compounds with broad-ranging applications in such diverse areas as medicinal chemistry, as auxiliaries in organic synthesis, in metallurgical applications, in aircraft deicing and brake fluids, and as antifog agents in photography. Although there are numerous approaches to N-substituted benzotriazoles, the essentially one general method to N-unsubstituted benzotriazoles is via diazotization of ortho -phenylenediamines, which can be limited by the availability of suitable precursors. Other methods to N-unsubstitued benzotriazoles are quite specialized. Although reduction of 1-hydroxy-1 H-benzotriazoles is known, the reactions are not particularly convenient or broadly applicable. This presents a limitation for easy access to and availability of diverse benzotri-ACHTUNGTRENUNGazoles. Herein, we demonstrate a new, broadly applicable method to diverse 1H-benzotriazoles via a mild diboron reagent-mediated deoxygenation of 1-hydroxy-1H-benzotriazoles. We have also evaluated sequential deoxygenation and Pd-mediated C-C and C-N bond formation as a one-pot process for further diversification of the benzotriazole moiety. However, the results indicated that purification of the deoxygenation product prior to the Pd-mediated reaction is critical to the success of such reactions. The overall chemistry allows for facile access to a variety of new benzotriazoles. Along with the several examples presented, a discussion of the advantages of the approaches is described, as is also a possible mechanism for the deoxygenation process.
- Gurram, Venkateshwarlu,Akula, Hari K.,Garlapati, Ramesh,Pottabathini, Narender,Lakshman, Mahesh K.
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p. 451 - 462
(2015/03/05)
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- Design, synthesis and determination of antifungal activity of 5(6)-substituted benzotriazoles
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In an effort to find inhibitors that are effective against both Candida and Aspergillus spp., a series of 5(6)-(un)substituted benzotriazole analogs, represented by compounds 3a-3h and 3b′-3f′, were prepared using a crystalline oxirane intermediate 1 previously synthesized in our laboratory. All the compounds were evaluated for inhibitory activity against various species of Candida and Aspergillus. Compounds 3b′ (5,6-dimethylbenzotriazol-2-yl derivative), 3d (5-chlorobenzotriazol-1-yl derivative) and 3e′ (6-methylbenzotriazol-1-yl derivative) exhibited potent antifungal activity, with the MICs for Candida spp. and Aspergillus niger, ranging from 1.6 μg/mL to 25 μg/mL and 12.5 μg/mL to 25 μg/mL, respectively. The present work describes the design, synthesis, regioisomer characterization (through COSY and NOESY 2D-NMR spectroscopy and single molecule X-ray crystallography), antifungal evaluation, molecular docking, and structure-activity relationships of the various 5(6)-(un)substituted benzotriazole analogs.
- Patel, Pallav D.,Patel, Maulik R.,Kocsis, Bela,Kocsis, Erika,Graham, Steven M.,Warren, Andrew R.,Nicholson, Stacia M.,Billack, Blase,Fronczek, Frank R.,Talele, Tanaji T.
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supporting information; experimental part
p. 2214 - 2222
(2010/09/08)
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- Applications of 1-Alkoxycarbonyl- and 1-Acyl-v-triazolopyridines as Acylating Reagents
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Selective N-protection of hydroxyamino esters has been readily achieved using 1-alkoxycarbonyl- or 1-acyl-v-triazolopyridines.The amide-type triazolides reacted with alcohols in the presence of DBU at room temperature to afford in high yields the corresponding esters.The different reactivity of 1- and 3-alkoxycarbonyl derivatives of the title bicyclic system toward primary amines has been further investigated.
- Torrini, Ines,Zecchini, Giampiero Pagani,Agrosi, Francesco,Paradisi, Mario Paglialunga
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p. 1459 - 1463
(2007/10/02)
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