Repositioning of the antipsychotic trifluoperazine: Synthesis, biological evaluation and in silico study of trifluoperazine analogs as anti-glioblastoma agents

Seokmin Kang, Jung Moo Lee, Borami Jeon, Ahmed Elkamhawy, Sora Paik, Jinpyo Hong, Soo Jin Oh, Sun Ha Paek, Changjoon Lee, Ahmed H.E. Hassan, Sang Soo Kang, Eun Joo Roh

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11 Citations (Scopus)

Abstract

Repositioning of the antipsychotic drug trifluoperazine for treatment of glioblastoma, an aggressive brain tumor, has been previously suggested. However, trifluoperazine did not increase the survival time in mice models of glioblastoma. In attempt to identify an effective trifluoperazine analog, fourteen compounds have been synthesized and biologically in vitro and in vivo assessed. Using MTT assay, compounds 3dc and 3dd elicited 4–5 times more potent inhibitory activity than trifluoperazine with IC50 = 2.3 and 2.2 μM against U87MG glioblastoma cells, as well as, IC50 = 2.2 and 2.1 μM against GBL28 human glioblastoma patient derived primary cells, respectively. Furthermore, they have shown a reasonable selectivity for glioblastoma cells over NSC normal neural cell. In vivo evaluation of analog 3dc confirmed its advantageous effect on reduction of tumor size and increasing the survival time in brain xenograft mouse model of glioblastoma. Molecular modeling simulation provided a reasonable explanation for the observed variation in the capability of the synthesized analogs to increase the intracellular Ca2+ levels. In summary, this study presents compound 3dc as a proposed new tool for the adjuvant chemotherapy of glioblastoma.

Original languageEnglish
Pages (from-to)186-198
Number of pages13
JournalEuropean Journal of Medicinal Chemistry
Volume151
DOIs
Publication statusPublished - 2018 May 10

Keywords

  • Brain cancer
  • Calcium
  • Glioblastoma
  • Orthotopic brain xenograft mouse model
  • Trifluoperazine
  • Trifluoperazine analogs

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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    Kang, S., Lee, J. M., Jeon, B., Elkamhawy, A., Paik, S., Hong, J., Oh, S. J., Paek, S. H., Lee, C., Hassan, A. H. E., Kang, S. S., & Roh, E. J. (2018). Repositioning of the antipsychotic trifluoperazine: Synthesis, biological evaluation and in silico study of trifluoperazine analogs as anti-glioblastoma agents. European Journal of Medicinal Chemistry, 151, 186-198. https://doi.org/10.1016/j.ejmech.2018.03.055