3-Aryl-2-[1 H-benzotriazol-1-yl]acrylonitriles: A novel class of potent tubulin inhibitors

• Published in: European journal of medicinal chemistry Vol. 46; no. 9; pp. 4151 - 4167
• Main Authors: Carta, Antonio, Briguglio, Irene, Piras, Sandra, Boatto, Giampiero, La Colla, Paolo, Loddo, Roberta, Tolomeo, Manlio, Grimaudo, Stefania, Di Cristina, Antonietta, Pipitone, Rosaria Maria, Laurini, Erik, Paneni, Maria Silvia, Posocco, Paola, Fermeglia, Maurizio, Pricl, Sabrina
• Format: Journal Article
• Language: English
• Published: PARIS Elsevier Masson SAS 01.09.2011; Elsevier
• Subjects: 3-Aryl-2-[1 H-benzotriazol-1-yl]acrylonitriles; Acrylonitrile - chemistry; Acrylonitrile - pharmacology; Antineoplastic agents; Antiproliferative activity; Binding, Competitive; Biological and medical sciences; Cell Cycle; Cell cycle distribution; Chemistry, Medicinal; Colchicine; Colchicine - chemistry; Gas Chromatography-Mass Spectrometry; General aspects; Homology studies; Humans; K562 Cells; Life Sciences & Biomedicine; Magnetic Resonance Spectroscopy; Medical sciences; Models, Molecular; Molecular modeling study; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Podophyllotoxin; Science & Technology; Structure-Activity Relationship; Triazoles - chemistry; Tubulin; Tubulin - drug effects; Molecular modeling study; Tubulin; Cell cycle distribution; Antiproliferative activity; Podophyllotoxin; Homology studies; Colchicine; 3-Aryl-2-[1 H-benzotriazol-1-yl]acrylonitriles; ANTIMYCOBACTERIAL ACTIVITY; MOLECULAR-DYNAMICS; DEPENDENT RNA-POLYMERASE; HEPATITIS-C-VIRUS; ANTIMITOTIC AGENTS; FREE-ENERGIES; BIOLOGICAL EVALUATION; GENERALIZED BORN; 3-Aryl-2-[1H-benzotriazol-1-yl]acrylonitriles; GASTROINTESTINAL STROMAL TUMORS; PHARMACOPHORE MODEL; Antineoplastic agent; Benzotriazole derivatives; Solid tumor; 3-Aryl-2-[1H-benzotriazol-1-yl] acrylonitriles; Nitrile; Nitrogen heterocycle; Leukemia; Cytotoxicity; Homology; Modeling; Structure activity relation; Chlorine Organic compounds; Vinylic compound; Cell cycle; Molecular model; Bicyclic compound; Binding mode; Aromatic compound; Chemical synthesis; Antimitotic; Tumor cell; Human; Ligand binding; Benzene derivatives; Antitubulin; In vitro; Cell line
• DOI: 10.1016/j.ejmech.2011.06.018
• ISSN: 0223-5234

During a screening for compounds that could act against Mycobacterium tuberculosis, a series of new cellular antiproliferative agents was identified. The most cytotoxic molecules were evaluated against a panel of human cell lines derived from hematological and solid human tumors. In particular, ( E)-2-(1 H-benzo[ d] [1,2,3]triazol-1-yl)-3-(4-methoxyphenyl)acrylonitrile ( 1) was found to be of a potency comparable to etoposide and greater than 6-mercaptopurine in all cell lines tested. Accordingly, a synthesis of a new series of ( E)-2-(5,6-dichloro-1 H-benzo[ d] [1,2,3]triazol-1-yl)-3-(4-R-phenyl)acrylonitriles was conducted in order to extend the studies of structure-activity relationship (SAR) for this class of molecules. With the aim to evaluate if 3-aryl-2-[1 H-benzotriazol-1-yl]acrylonitriles were able to act like tubulin binding agents, the effects on cell cycle distribution of the most active compounds ( 1, 2a, 3 and 4) were analyzed in K562 cells. A detailed molecular modeling study of the putative binding mode of this series of compounds on tubulin is also reported. Detailed view of tubulin residues interacting with the lead compound. [Display omitted] ► The 3-Aryl-2-[1 H-benzotriazol-1-yl]acrylonitriles showed an antiproliferative activity. ► We investigated their effects on cell cycle distribution. ► They showed a tubulin binding activity, confirmed through [ 3H]Colchicine competition binding assay. ► We extended the studies of structure-activity relationship for this molecular class. ► The putative binding modes on human β-tubulin was predicted.