1. Academic Validation
  2. Identification of HUHS190, a human naftopidil metabolite, as a novel anti-bladder cancer drug

Identification of HUHS190, a human naftopidil metabolite, as a novel anti-bladder cancer drug

  • Bioorg Med Chem Lett. 2020 Jan 1;30(1):126744. doi: 10.1016/j.bmcl.2019.126744.
Tadashi Shimizu 1 Keiko Yamaguchi 2 Momoka Yamamoto 2 Rina Kurioka 2 Yukari Kino 2 Wataru Matsunaga 3 Syuhei Nakao 4 Hiroshi Fukuhara 5 Akito Tanaka 1 Akinobu Gotoh 3 Miyuki Mabuchi 6
Affiliations

Affiliations

  • 1 Laboratory of Chemical Biology, Advanced Medicinal Research Center, Hyogo University of Health Sciences, Kobe, Hyogo, Japan; School of Pharmacy, Hyogo University of Health Sciences, Kobe, Hyogo, Japan.
  • 2 School of Pharmacy, Hyogo University of Health Sciences, Kobe, Hyogo, Japan.
  • 3 Laboratory of Cell and Gene Therapy, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
  • 4 Synthetic Organic Chemistry Laboratory, RIKEN Cluster for Pioneering Research, Wako, Saitama, Japan.
  • 5 Department of Urology, Kyorin University, Tokyo, Japan.
  • 6 Laboratory of Chemical Biology, Advanced Medicinal Research Center, Hyogo University of Health Sciences, Kobe, Hyogo, Japan. Electronic address: mabuchi@huhs.ac.jp.
Abstract

We carried out structure-activity relationship study on anti-cancer effects of naftopidil (1) and its metabolites, resulted in identification of 1-(4-hydroxy-2-methoxyphenyl)piperazin-1-yl)-3-(naphthalen-1-yloxy) propan-2-ol (2, HUHS190), a major human metabolite of 1, which exhibited the most selective toxicities between against normal and Cancer cells (Table 1). 2 was more hydrophilic compared to 1, was enough to be prepared in high concentration solution of more than 100 μM in saline for an intravesical instillation drug. Moreover, serum concentration of 2 was comparable to that of 1, an oral preparation drug, after oral administration at 32 mg/kg (Fig. 3). Both of 1 and 2 showed broad-spectrum anti-cancer activities in vitro, for example, 1 and 2 showed inhibitory activity IC50 = 21.1 μM and 17.2 μM for DU145, human prostate Cancer cells, respectively, and IC50 = 18.5 μM and 10.5 μM for T24 cells, human bladder Cancer cells. In this study, we estimated Anticancer effects of 2 in a bladder Cancer model after intravesical administration similar to clinical cases. A single intravesical administration of 2 exhibited the most potent inhibitory activities among the clinical drugs for bladder cancers, BCG and Pirarubicin, without obvious side effects and toxicity (Fig. 4). Thus, HUHS190 (2) can be effective for patients after post-TURBT therapy of bladder Cancer without side effects, unlike the currently available clinical drugs.

Keywords

Active metabolite; Anti-bladder cancer drug; BCG; HUHS190; Intravesical administration; Naftopidil; Pirarubicin; Repositioning; Structure-activity relationship.

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