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. 2013 Apr:62:40-50.
doi: 10.1016/j.ejmech.2013.01.006. Epub 2013 Jan 11.

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

Maja D Vitorović-Todorović  1 , Aleksandra Erić-Nikolić, Branka Kolundžija, Ernest Hamel, Slavica Ristić, Ivan O Juranić, Branko J Drakulić
Affiliations

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

Maja D Vitorović-Todorović et al. Eur J Med Chem. 2013 Apr.

Abstract

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.

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Figures

Fig 1
Fig 1
Structures of some compounds with the ketovinyl moiety that have antiproliferative activity: (I) chalcones, (II) flavones, (III) 4-aminochalcone maleamic acid, (IV) 4-aminochalcone maleimides, (V) phenylcinnamides, (VI) cinnamoyl anthranilates.
Scheme 1
Scheme 1
Synthetic pathway to compounds 1–29 (Table 1). Reagents: (a) AlCl3 in CH2Cl2; (b) POCl3, dry THF. For compounds 8 and 17, cyclohexylamine was used to obtain the corresponding aroylacrylic acid amides (D). Benzylamine was used to obtain derivatives 9, 10, 15 and 17. For the rest of the compounds, aniline or substituted anilines were used.
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