2. Academic Validation
  3. Triazolopyridinyl-acrylonitrile derivatives as antimicrotubule agents: Synthesis, in vitro and in silico characterization of antiproliferative activity, inhibition of tubulin polymerization and binding thermodynamics

Triazolopyridinyl-acrylonitrile derivatives as antimicrotubule agents: Synthesis, in vitro and in silico characterization of antiproliferative activity, inhibition of tubulin polymerization and binding thermodynamics

  • Eur J Med Chem. 2017 Dec 1:141:460-472. doi: 10.1016/j.ejmech.2017.09.065.
Irene Briguglio 1,  Erik Laurini 2,  Maria Antonietta Pirisi 1,  Sandra Piras 1,  Paola Corona 1,  Maurizio Fermeglia 2,  Sabrina Pricl 3,  Antonio Carta 4
Affiliations

Affiliations

  • 1 Dipartimento di Chimica e Farmacia, Università degli Studi di Sassari, via Muroni 23A, 07100 Sassari, SS, Italy.
  • 2 Molecular Simulation Engineering (MOSE) Laboratory, DEA, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy; National Interuniversity Consortium for Material Science and Technology (INSTM), Research Unit MOSE-DEA, University of Trieste, 34127 Trieste, Italy.
  • 3 Molecular Simulation Engineering (MOSE) Laboratory, DEA, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy; National Interuniversity Consortium for Material Science and Technology (INSTM), Research Unit MOSE-DEA, University of Trieste, 34127 Trieste, Italy. Electronic address: sabrina.pricl@dia.units.it.
  • 4 Dipartimento di Chimica e Farmacia, Università degli Studi di Sassari, via Muroni 23A, 07100 Sassari, SS, Italy. Electronic address: acarta@uniss.it.
PMID: 29055869 DOI: 10.1016/j.ejmech.2017.09.065
Abstract

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.

Keywords

Antiproliferative activity; Fluorescence-based assays; Isothermal titration calorimetry; Molecular modeling; Triazolo[4,5-b/c]pyridin-acrylonitriles; Tubulin polymerization.

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