Synthesis of N-acyl Derivatives of Aminocombretastatin A-4 and Study of their Interaction with Tubulin and Downregulation of c-Myc.

Medicinal Chemistry
Raül AgutJ Alberto Marco

Abstract

Six N-acyl derivatives of aminocombretastatin A-4 have been synthesized and evaluated according to their interaction with tubulin and as c-Myc downregulators. In search of new promising anti-cancer agents. This study is focused on the synthesis and the biological evaluation of N-acyl derivatives of aminocombretastatin A-4 (CA-4). Docking studies were carried out to find out whether the synthetic derivatives could bind to tubulin at the colchicine site in a conformation similar to that of CA- 4. The synthetic derivatives' effect on the proliferation of several cancer cells and non-cancer cells has been measured. Their effect on tubulin polymerization, cell cycle distribution, the microtubule network and c-Myc expression has also been evaluated. A set of six N-acyl derivatives was achieved by means of a peptide-type coupling of aminocombretastatin A-4 and the corresponding carboxylic acid. The synthetic compounds' ability to inhibit cell proliferation was measured by MTT assay against three human carcinoma cell lines (colorectal HT-29, lung A549, and breast adenocarcinoma MCF-7) and one non-tumor cell line (HEK- 293). Turbidimetry time-course measurements evaluated the inhibition of tubulin polymerization. The action of the synth...Continue Reading

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