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; C. Justin Lee; Ahmed H.E. Hassan; Sang Soo Kang; Eun Joo Roh

doi:10.1016/j.ejmech.2018.03.055

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, C. Justin Lee, Ahmed H.E. Hassan, Sang Soo Kang, Eun Joo Roh

KU-KIST Graduate School of Converging Science and Technology

Research output: Contribution to journal › Article › peer-review

29 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 language	English
Pages (from-to)	186-198
Number of pages	13
Journal	European Journal of Medicinal Chemistry
Volume	151
DOIs	https://doi.org/10.1016/j.ejmech.2018.03.055
Publication status	Published - 2018 May 10

Bibliographical note

Funding Information:
This study was supported by the KIST Institutional programs (Grant No. 2E28010 ) from Korea Institute of Science and Technology (to E.J. Roh), the Creative Fusion Research Program through the Creative Allied Project funded by the National Research Council of Science & Technology ( CAP-12-1-KIST ) (to E.J. Roh), the National Research Foundation of Korea (NRF), a grant funded by the Korean Government ( MEST ) ( 2013R1A2A2A01068964 ) (to S.S. Kang), the Creative Research Initiative Program, the Korean National Research Foundation ( 2015R1A3A2066619 ) (to C.J. Lee), the KU- KIST Graduate School of Science and Technology program ( R1435283 ) (to C.J. Lee), KIST Institutional Grant ( 2E26860 ) (to C.J. Lee), the Korea Healthcare Technology R&D Project funded by the Ministry of Health & Welfare (grant no. HI11C21100200 ) (to S.H. Paek), the Technology Innovation Program funded by the Ministry of Trade, Industry & Energy (grant no. 10050154 , Business Model Development for Personalized Medicine Based on Integrated Genome and Clinical Information) (to S.H. Paek), and the Bio & Medical Technology Development Program of the NRF funded by the Korean government (MSIP) (grant no. 2015M3C7A1028926 ) (to S.H. Paek).

Funding Information:
This study was supported by the KIST Institutional programs (Grant No. 2E28010) from Korea Institute of Science and Technology (to E.J. Roh), the Creative Fusion Research Program through the Creative Allied Project funded by the National Research Council of Science & Technology (CAP-12-1-KIST) (to E.J. Roh), the National Research Foundation of Korea (NRF), a grant funded by the Korean Government (MEST) (2013R1A2A2A01068964) (to S.S. Kang), the Creative Research Initiative Program, the Korean National Research Foundation (2015R1A3A2066619) (to C.J. Lee), the KU-KIST Graduate School of Science and Technology program (R1435283) (to C.J. Lee), KIST Institutional Grant (2E26860) (to C.J. Lee), the Korea Healthcare Technology R&D Project funded by the Ministry of Health & Welfare (grant no. HI11C21100200) (to S.H. Paek), the Technology Innovation Program funded by the Ministry of Trade, Industry & Energy (grant no. 10050154, Business Model Development for Personalized Medicine Based on Integrated Genome and Clinical Information) (to S.H. Paek), and the Bio & Medical Technology Development Program of the NRF funded by the Korean government (MSIP) (grant no. 2015M3C7A1028926) (to S.H. Paek).

Publisher Copyright:
© 2018 Elsevier Masson SAS

Keywords

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

ASJC Scopus subject areas

Pharmacology
Drug Discovery
Organic Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.ejmech.2018.03.055

Cite this

Kang, S., Lee, J. M., Jeon, B., Elkamhawy, A., Paik, S., Hong, J., Oh, S. J., Paek, S. H., Lee, C. J., 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

Kang, S, Lee, JM, Jeon, B, Elkamhawy, A, Paik, S, Hong, J, Oh, SJ, Paek, SH, Lee, CJ, Hassan, AHE, Kang, SS & Roh, EJ 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, vol. 151, pp. 186-198. https://doi.org/10.1016/j.ejmech.2018.03.055

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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.",

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author = "Seokmin Kang and Lee, {Jung Moo} and Borami Jeon and Ahmed Elkamhawy and Sora Paik and Jinpyo Hong and Oh, {Soo Jin} and Paek, {Sun Ha} and Lee, {C. Justin} and Hassan, {Ahmed H.E.} and Kang, {Sang Soo} and Roh, {Eun Joo}",

note = "Funding Information: This study was supported by the KIST Institutional programs (Grant No. 2E28010 ) from Korea Institute of Science and Technology (to E.J. Roh), the Creative Fusion Research Program through the Creative Allied Project funded by the National Research Council of Science & Technology ( CAP-12-1-KIST ) (to E.J. Roh), the National Research Foundation of Korea (NRF), a grant funded by the Korean Government ( MEST ) ( 2013R1A2A2A01068964 ) (to S.S. Kang), the Creative Research Initiative Program, the Korean National Research Foundation ( 2015R1A3A2066619 ) (to C.J. Lee), the KU- KIST Graduate School of Science and Technology program ( R1435283 ) (to C.J. Lee), KIST Institutional Grant ( 2E26860 ) (to C.J. Lee), the Korea Healthcare Technology R&D Project funded by the Ministry of Health & Welfare (grant no. HI11C21100200 ) (to S.H. Paek), the Technology Innovation Program funded by the Ministry of Trade, Industry & Energy (grant no. 10050154 , Business Model Development for Personalized Medicine Based on Integrated Genome and Clinical Information) (to S.H. Paek), and the Bio & Medical Technology Development Program of the NRF funded by the Korean government (MSIP) (grant no. 2015M3C7A1028926 ) (to S.H. Paek). Funding Information: This study was supported by the KIST Institutional programs (Grant No. 2E28010) from Korea Institute of Science and Technology (to E.J. Roh), the Creative Fusion Research Program through the Creative Allied Project funded by the National Research Council of Science & Technology (CAP-12-1-KIST) (to E.J. Roh), the National Research Foundation of Korea (NRF), a grant funded by the Korean Government (MEST) (2013R1A2A2A01068964) (to S.S. Kang), the Creative Research Initiative Program, the Korean National Research Foundation (2015R1A3A2066619) (to C.J. Lee), the KU-KIST Graduate School of Science and Technology program (R1435283) (to C.J. Lee), KIST Institutional Grant (2E26860) (to C.J. Lee), the Korea Healthcare Technology R&D Project funded by the Ministry of Health & Welfare (grant no. HI11C21100200) (to S.H. Paek), the Technology Innovation Program funded by the Ministry of Trade, Industry & Energy (grant no. 10050154, Business Model Development for Personalized Medicine Based on Integrated Genome and Clinical Information) (to S.H. Paek), and the Bio & Medical Technology Development Program of the NRF funded by the Korean government (MSIP) (grant no. 2015M3C7A1028926) (to S.H. Paek). Publisher Copyright: {\textcopyright} 2018 Elsevier Masson SAS",

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doi = "10.1016/j.ejmech.2018.03.055",

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AU - Jeon, Borami

AU - Elkamhawy, Ahmed

AU - Paik, Sora

AU - Hong, Jinpyo

AU - Oh, Soo Jin

AU - Paek, Sun Ha

AU - Lee, C. Justin

AU - Hassan, Ahmed H.E.

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AU - Roh, Eun Joo

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N2 - 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.

AB - 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.

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

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