Inhibition of human equilibrative nucleoside transporters by 4-((4-(2-fluorophenyl)piperazin-1-yl)methyl)-6-imino-N-(naphthalen-2-yl)-1,3,5-triazin-2-amine

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• 作者：Philip C.T. Tang^a ; Cui Yang^b ; Rachel Wai-Sum Li^a ; Simon Ming-Yuen Lee^c ; Maggie Pui-man Hoi^c ; Shun-Wan Chan^d ; Yiu-Wa Kwan^e ; Chung-Ming Tse^f ; George Pak-Heng Leung^a ; ^{gphleung@hku.hk" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Cancer ; Cardiovascular disease ; Equilibrative nucleoside transporters ; Inhibitor
• 刊名：European Journal of Pharmacology
• 出版年：2016
• 出版时间：15 November 2016
• 年：2016
• 卷：791
• 期：Complete
• 页码：544-551
• 全文大小：1244 K

文摘

Equilibrative nucleoside transporters (ENTs) play a crucial role in the transport of nucleoside and nucleoside analogues, which are important for nucleotide synthesis and chemotherapy. In addition, ENTs regulate extracellular adenosine levels in the vicinity of its receptors and hence influence adenosine-related functions. The clinical applications of ENT inhibitors in the treatment of cardiovascular diseases and cancer therapy have been explored in numerous studies. However, all ENT inhibitors to date are selective for ENT1 but not ENT2. In the present study, we investigated the novel compound 4-((4-(2-fluorophenyl)piperazin-1-yl)methyl)-6-imino-N-(naphthalen-2-yl)-1,3,5-triazin-2-amine (FPMINT) as an inhibitor of ENT1 and ENT2. Nucleoside transporter-deficient PK15NTD cells stably expressing ENT1 and ENT2 showed that FPMINT inhibited [³H]uridine and [³H]adenosine transport through both ENT1 and ENT2 in a concentration-dependent manner. The IC₅₀ value of FPMINT for ENT2 was 5-10-fold less than for ENT1, and FPMINT could not be displaced with excess washing. Kinetic studies revealed that FPMINT reduced V_max of [³H]uridine transport in ENT1 and ENT2 without affecting K_M. Therefore, we conclude that FPMINT inhibits ENTs in an irreversible and non-competitive manner. Although already selective for ENT2 over ENT1, further modification of the chemical structure of FPMINT may lead to even better ENT2-selective inhibitors of potential clinical, physiological and pharmacological importance.