Design, synthesis and biological evaluation of benzoylacrylic acid shikonin ester derivatives as irreversible dual inhibitors of tubulin and EGFR

Bioorg Med Chem. 2019 Dec 1;27(23):115153. doi: 10.1016/j.bmc.2019.115153. Epub 2019 Oct 15.

Abstract

In this study, a series of shikonin derivatives combined with benzoylacrylic had been designed and synthesized, which showed an inhibitory effect on both tubulin and the epidermal growth factor receptor (EGFR). In vitro EGFR and cell growth inhibition assay demonstrated that compound PMMB-317 exhibited the most potent anti-EGFR (IC50 = 22.7 nM) and anti-proliferation activity (IC50 = 4.37 μM) against A549 cell line, which was comparable to that of Afatinib (EGFR, IC50 = 15.4 nM; A549, IC50 = 6.32 μM). Our results on mechanism research suggested that, PMMB-317 could induce the apoptosis of A549 cells in a dose- and time-dependent manner, along with decrease in mitochondrial membrane potential (MMP), production of ROS and alterations in apoptosis-related protein levels. Also, PMMB-317 could arrest cell cycle at G2/M phase to induce cell apoptosis, and inhibit the EGFR activity through blocking the signal transduction downstream of the mitogen-activated protein MAPK pathway and the anti-apoptotic kinase AKT pathway; typically, such results were comparable to those of afatinib. In addition, PMMB-317 could suppress A549 cell migration through the Wnt/β-catenin signaling pathway in a dose-dependent manner. Additionally, molecular docking simulation revealed that, PMMB-317 could simultaneously combine with EGFR protein (5HG8) and tubulin (1SA0) through various forces. Moreover, 3D-QSAR study was also carried out, which could optimize our compound through the structure-activity relationship analysis. Furthermore, the in vitro and in vivo results had collectively confirmed that PMMB-317 might serve as a promising lead compound to further develop the potential therapeutic anticancer agents.

Keywords: Afatinib (PubChem CID: 10184653); Anticancer; Benzene (PubChem CID: 241); Benzoylacrylic; Bromobenzene (PubChem CID: 7961); Chlorobenzene (PubChem CID: 7964); Colchicine (PubChem CID: 6167); Epidermal growth factor receptor; Fluorobenzene (PubChem CID: 10008); Maleic anhydride (PubChem CID: 7923); Methylbenzene (PubChem CID: 1140); Paclitaxel (PubChem CID: 36314); Shikonin; Shikonin (PubChem CID: 479503); Tubulin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Acrylates / chemistry
  • Acrylates / pharmacology*
  • Acrylates / therapeutic use
  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Apoptosis / drug effects
  • Benzoates / chemistry
  • Benzoates / pharmacology*
  • Benzoates / therapeutic use
  • Drug Design
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / metabolism
  • Humans
  • Mice, Nude
  • Molecular Docking Simulation
  • Naphthoquinones / chemistry
  • Naphthoquinones / pharmacology*
  • Naphthoquinones / therapeutic use
  • Neoplasms / drug therapy
  • Neoplasms / metabolism
  • Tubulin / metabolism
  • Tubulin Modulators / chemistry
  • Tubulin Modulators / pharmacology*
  • Tubulin Modulators / therapeutic use

Substances

  • Acrylates
  • Antineoplastic Agents
  • Benzoates
  • Naphthoquinones
  • Tubulin
  • Tubulin Modulators
  • benzoylacrylic acid
  • shikonin
  • EGFR protein, human
  • ErbB Receptors