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.
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鉴定 HUHS190（一种人萘哌地尔代谢物）作为一种新型抗膀胱癌药物。
DOI：
10.1016/j.bmcl.2019.126744
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发表时间：
2019
影响因子：
2.7
通讯作者：
Miyuki Mabuchi
中科院分区：
文献类型：
--
作者：
Tadashi Shimizu;K. Yamaguchi;Momoka Yamamoto;Rina Kurioka;Yukari Kino;Wataru Matsunaga;S. Nakao;H. Fukuhara;A. Tanaka;A. Gotoh;Miyuki Mabuchi
我们对萘哌地尔(1)及其代谢物的抗癌作用进行了构效关系研究，鉴定出1的主要人体代谢物1-(4-hydroxy-2-methoxyphenyl)piperazin-1-yl)-3-(naphthalen-1-yloxy)丙醇-2-醇(2，HUHS190)，它对正常细胞和癌细胞具有最强的选择性毒性(表1)。2比1更亲水，足以在100 μM以上的生理盐水的高浓度溶液中制备成膀胱内滴注药物。此外，口服32 mg/kg后，2的血药浓度与口服制剂药物1相当(图3)。化合物1和2对人前列腺癌DU145细胞的抑制活性IC50分别为 21.1 μM和17.2 μM，对人膀胱癌细胞T24的抑制活性IC50分别为 18.5 μM和10.5 μM。在这项研究中，我们在膀胱癌模型中评估了与临床病例相似的膀胱内给药2的抗癌作用。在治疗膀胱癌的临床药物卡介苗和吡柔比星中，单次膀胱内给药2的抑制活性最强，没有明显的副作用和毒性(图4)。因此，与目前可用的临床药物不同，HUHS190(2)可以有效地用于膀胱癌TURBT后治疗后的患者，而没有副作用。
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 of1, which exhibited the most selective toxicities between against normal and cancer cells (Table 1).2was more hydrophilic compared to1, was enough to be prepared in high concentration solution of more than 100 μM in saline for an intravesical instillation drug. Moreover, serum concentration of2was comparable to that of1, an oral preparation drug, after oral administration at 32 mg/kg (Fig. 3). Both of1and2showed broad-spectrum anti-cancer activitiesin vitro, for example,1and2showed 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 of2in a bladder cancer model after intravesical administration similar to clinical cases. A single intravesical administration of2exhibited 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.
影响因子：
6.4
作者：
Kanda, Hideki;Ishii, Kenichiro;Sugimura, Yoshiki
通讯作者：
Sugimura, Yoshiki