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Design, synthesis and biological evaluation of benzoylacrylic acid shikonin ester derivatives as irreversible dual inhibitors of tubulin and EGFR.
Sun, Wen-Xue; Han, Hong-Wei; Yang, Min-Kai; Wen, Zhong-Ling; Wang, Yin-Song; Fu, Jiang-Yan; Lu, Yun-Ting; Wang, Ming-Yue; Bao, Jia-Xin; Lu, Gui-Hua; Qi, Jin-Liang; Wang, Xiao-Ming; Lin, Hong-Yan; Yang, Yong-Hua.
Afiliación
  • Sun WX; State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, PR China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, PR China.
  • Han HW; State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, PR China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, PR China.
  • Yang MK; State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, PR China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, PR China.
  • Wen ZL; State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, PR China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, PR China.
  • Wang YS; State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, PR China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, PR China.
  • Fu JY; State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, PR China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, PR China.
  • Lu YT; State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, PR China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, PR China.
  • Wang MY; State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, PR China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, PR China.
  • Bao JX; State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, PR China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, PR China.
  • Lu GH; State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, PR China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, PR China.
  • Qi JL; State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, PR China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, PR China. Electronic addres
  • Wang XM; State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, PR China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, PR China. Electronic addres
  • Lin HY; State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, PR China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, PR China. Electronic addres
  • Yang YH; State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing 210023, PR China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, PR China. Electronic addres
Bioorg Med Chem ; 27(23): 115153, 2019 12 01.
Article en En | MEDLINE | ID: mdl-31648877
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/ß-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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Benzoatos / Acrilatos / Naftoquinonas / Moduladores de Tubulina / Antineoplásicos Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Bioorg Med Chem Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2019 Tipo del documento: Article Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Benzoatos / Acrilatos / Naftoquinonas / Moduladores de Tubulina / Antineoplásicos Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Bioorg Med Chem Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2019 Tipo del documento: Article Pais de publicación: Reino Unido