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

[Display omitted] 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 exhibi...

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Published in:	Bioorganic & medicinal chemistry letters Vol. 30; no. 1; p. 126744
Main Authors:	Shimizu, Tadashi, Yamaguchi, Keiko, Yamamoto, Momoka, Kurioka, Rina, Kino, Yukari, Matsunaga, Wataru, Nakao, Syuhei, Fukuhara, Hiroshi, Tanaka, Akito, Gotoh, Akinobu, Mabuchi, Miyuki
Format:	Journal Article
Language:	English
Published:	England Elsevier Ltd 01-01-2020
Subjects:	Active metabolite Animals Anti-bladder cancer drug Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use BCG Female HUHS190 Humans Intravesical administration Male Mice Naftopidil Naphthalenes - pharmacology Naphthalenes - therapeutic use Piperazines - pharmacology Piperazines - therapeutic use Pirarubicin Repositioning Structure-Activity Relationship Urinary Bladder Neoplasms - drug therapy Pirarubicin Structure-activity relationship Anti-bladder cancer drug BCG HUHS190 Active metabolite Repositioning Intravesical administration Naftopidil
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Summary:	[Display omitted] 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2019.126744