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

• Published in: European journal of medicinal chemistry 2017-12, Vol.141, p.460-472
• Main Authors: Briguglio, Irene, Laurini, Erik, Pirisi, Maria Antonietta, Piras, Sandra, Corona, Paola, Fermeglia, Maurizio, Pricl, Sabrina, Carta, Antonio
• Format: Article
• Language: English
• Subjects: Acrylonitrile - chemistry; Acrylonitrile - pharmacology; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antiproliferative activity; Binding Sites; Cell Line; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Fluorescence-based assays; Humans; Isothermal titration calorimetry; Models, Molecular; Molecular modeling; Molecular Structure; Polymerization - drug effects; Pyridines - chemistry; Pyridines - pharmacology; Structure-Activity Relationship; Thermodynamics; Triazoles - chemistry; Triazoles - pharmacology; Triazolo[4,5-b/c]pyridin-acrylonitriles; Tubulin - metabolism; Tubulin Modulators - chemistry; Tubulin Modulators - pharmacology; Tubulin polymerization
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2017.09.065

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. [Display omitted] •We present a series of E isomers of triazolo[4,5-b/c]pyridin-acrylonitrile derivatives.•All the derivates have been investigated for their antiproliferative activity.•Fluorescence-based assays prove that derivatives interfere with tubulin polymerization.•Isothermal titration calorimetry provides full tubulin/compound binding thermodynamics.•In silico modeling of interactions between tubulin and the title compounds is reported.