(E)-4-aryl-4-oxo-2-butenoic acid amides, chalcone-aroylacrylic acid chimeras: design, antiproliferative activity and inhibition of tubulin polymerization

• Published in: European journal of medicinal chemistry Vol. 62; pp. 40 - 50
• Main Authors: Vitorović-Todorović, Maja D, Erić-Nikolić, Aleksandra, Kolundžija, Branka, Hamel, Ernest, Ristić, Slavica, Juranić, Ivan O, Drakulić, Branko J
• Format: Journal Article
• Language: English
• Published: France 01-04-2013
• Subjects: Acrylates - chemistry; Acrylates - pharmacology; Amides - chemistry; Amides - pharmacology; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Cycle - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Chalcone - chemistry; Chalcone - pharmacology; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Fatty Acids, Monounsaturated - chemistry; Fatty Acids, Monounsaturated - pharmacology; HeLa Cells; Humans; K562 Cells; Male; Mice; Molecular Structure; Polymerization - drug effects; Structure-Activity Relationship; Tubulin - metabolism
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2013.01.006

Antiproliferative activity of twenty-nine (E)-4-aryl-4-oxo-2-butenoic acid amides against three human tumor cell lines (HeLa, FemX, and K562) is reported. Compounds showed antiproliferative activity in one-digit micromolar to submicromolar concentrations. The most active derivatives toward all the cell lines tested bear alkyl substituents on the aroyl moiety of the molecules. Fourteen compounds showed tubulin assembly inhibition at concentrations <20 μM. The most potent inhibitor of tubulin assembly was unsubstituted compound 1, with IC50 = 2.9 μM. Compound 23 had an oral LD50in vivo of 45 mg/kg in mice. Cell cycle analysis on K562 cells showed that compounds 1, 2 and 23 caused accumulation of cells in the G2/M phase, but inhibition of microtubule polymerization is not the principal mode of action of the compounds. Nevertheless, they may be useful leads for the design of a new class of antitubulin agents.