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

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

  • Eur J Med Chem. 2018 May 10:151:186-198. doi: 10.1016/j.ejmech.2018.03.055.
Seokmin Kang 1,  Jung Moo Lee 2,  Borami Jeon 3,  Ahmed Elkamhawy 4,  Sora Paik 5,  Jinpyo Hong 6,  Soo-Jin Oh 7,  Sun Ha Paek 8,  C Justin Lee 9,  Ahmed H E Hassan 10,  Sang Soo Kang 11,  Eun Joo Roh 12
Affiliations

Affiliations

  • 1 Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju, 52727, Republic of Korea.
  • 2 KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, 02841, Republic of Korea; Center for Neuroscience and Functional Connectomics, Brain Science Institute, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea.
  • 3 Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea.
  • 4 Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
  • 5 Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea; Department of Fundamental Pharmaceutical Sciences, College of Pharmacy, Kyung Hee University, Seoul, 02447, Republic of Korea.
  • 6 Center for Neuroscience and Functional Connectomics, Brain Science Institute, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea.
  • 7 Center for Neuroscience and Functional Connectomics, Brain Science Institute, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea; Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea.
  • 8 Department of Neurosurgery, College of Medicine, Seoul National University, Seoul, 08826, Republic of Korea.
  • 9 KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, 02841, Republic of Korea; Center for Neuroscience and Functional Connectomics, Brain Science Institute, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea; Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul, 02792, Republic of Korea.
  • 10 Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
  • 11 Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju, 52727, Republic of Korea. Electronic address: kangss@gnu.ac.kr.
  • 12 Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea; Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul, 02792, Republic of Korea. Electronic address: r8636@kist.re.kr.
PMID: 29614416 DOI: 10.1016/j.ejmech.2018.03.055
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.

Keywords

Brain cancer; Calcium; Glioblastoma; Orthotopic brain xenograft mouse model; Trifluoperazine; Trifluoperazine analogs.

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