Journal of Chemical Biology

, Volume 8, Issue 1, pp 5–9 | Cite as

Identification of a new pharmacological activity of the phenylpiperazine derivative naftopidil: tubulin-binding drug

  • Kenichiro IshiiEmail author
  • Yoshiki Sugimura
Original Article


The phenylpiperazine derivative naftopidil is an α1-adrenoceptor (AR) antagonist that has been used clinically to treat benign prostatic hyperplasia. In our drug repositioning research, naftopidil shows the unique growth-inhibitory effects. Naftopidil inhibits cell cycle progression not only in cancer cells, but also in fibroblasts and vascular endothelial cells. Naftopidil-inhibited cell cycle progression is independent of α1-AR expression in cells. Therefore, the antiproliferative effects of naftopidil may be due to the off-target effects of the drug. In this study, we attempted to identify the off-target molecules of naftopidil using the magnetic nanobeads, ferrite glycidyl metharcrylate (FG) beads. Similar to naftopidil, its derivatives TG09-01 and TG09-02, which were introduced with amino groups for immobilizing to FG beads, inhibited cell growth in human HT29 colon adenocarcinoma cells. Both derivatives were associated with inhibition of cell cycle progression in HT29 cells. This observation is consistent with that seen with naftopidil. Using TG09-02-immobilized FG beads, α- and β-tubulins were identified as the specific binding proteins of naftopidil. The tubulin polymerization assay clearly indicated that naftopidil bound directly to tubulin and inhibited the polymerization of tubulin. Other phenylpiperazine derivatives, such as RS100329, BMY7378, and KN-62, also inhibited the polymerization of tubulin. These results suggest that phenylpiperazine derivatives including naftopidil may have broad spectrum of cellular cytotoxicity in various types of cells. In addition, the tubulin polymerization-inhibiting activity of phenylpiperazine derivatives may be a specific feature of the phenylpiperazine-based structure. These findings can allow us to design and synthesize new tubulin-binding drugs derived from naftopidil as a lead compound.


Naftopidil Phenylpiperazine-based structure Off-target effects Magnetic nanobeads Tubulin polymerization 



We thank Mrs. Yumi Yoshikawa for technical support. This work was supported by Grants-in-Aid from the Ministry of Education for Science and Culture of Japan (23791751).


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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Department of Nephro-Urologic Surgery and AndrologyMie University Graduate School of MedicineTsuJapan
  2. 2.Department of Oncologic PathologyMie University Graduate School of MedicineTsuJapan

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