Synthesis and anti-proliferative activity of new E7010 tethered urea congeners as potential tubulin inhibitors and apoptosis inducers

TL;DR

Researchers designed and tested new urea compounds that show strong anti-cancer activity by inhibiting tubulin and inducing cell death.

Contribution

The paper introduces new E7010-derived urea analogues with potent anti-proliferative activity and a clear mechanism of tubulin inhibition.

Findings

Compound 6q showed strong cytotoxicity against multiple cancer cell lines with IC50 values between 2.03 and 8.14 µM.

Compound 6q disrupts microtubule structure and arrests the cell cycle at the G2/M phase.

Molecular docking studies suggest 6q binds to the colchicine site of β-tubulin and induces apoptosis in A549 cells.

Abstract

A series of twenty-four 1-phenyl-3-(2-phenylpyridin-3-yl)urea congeners (6a–x) have been designed and synthesized. All these compounds were evaluated for their anti-cancer activity against four human cancer cell lines, including prostate cancer (DU-145), lung cancer (A549), cervical cancer (HeLa) and breast cancer (MDA-MB-231). Compound 6q emerged as the most potent in the series, showing consistently strong cytotoxicity against all tested cell lines, with IC50 values ranging from 2.03 to 8.14 µM. Further investigation into the mechanism of action of compound 6q revealed it can arrest cell cycle progression at the G2/M phase. Immunocytochemistry studies showed a notable disruption of microtubule structure in cells treated with 6q. Molecular docking studies provided strong evidence that compound 6q works by binding to the colchicine binding site of β-tubulin, with sequential hydrophilic and hydrophobic interactions. Additionally, the effects of 6q on cell migration and its ability to induce apoptosis in A549 cells were examined using nuclear and mitochondrial staining techniques.

E7010-derived urea analogues were designed via sulfonamide-to-urea replacement and aniline trimming, yielding potent tubulin inhibitors and apoptosis inducers.

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