title: 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.
abstract: 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 IC50value 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 Vmaxof [3H]uridine transport in ENT1 and ENT2 without affecting KM. 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.
authors.affiliation: Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China.
authors.forename: Philip C T
authors.initials: PCT
authors.lastname: Tang
authors.affiliation: Ethnic Drug Screening & Pharmacology Center, Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission & Ministry of Education, Yunnan Minzu University, Kunming 650500, China.
authors.forename: Cui
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China.
authors.forename: Rachel Wai-Sum
authors.initials: RW
authors.lastname: Li
authors.affiliation: Institute of Chinese Medical Sciences, University of Macau, Macao, China.
authors.forename: Simon Ming-Yuen
authors.initials: SM
authors.lastname: Lee
authors.affiliation: Institute of Chinese Medical Sciences, University of Macau, Macao, China.
authors.forename: Maggie Pui-Man
authors.initials: MP
authors.lastname: Hoi
authors.affiliation: Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China.
authors.forename: Shun-Wan
authors.initials: SW
authors.lastname: Chan
authors.affiliation: School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Yiu-Wa
authors.initials: YW
authors.lastname: Kwan
authors.affiliation: Department of Medicine, Division of Gastroenterology, School of Medicine, The Johns Hopkins University, United States.
authors.forename: Chung-Ming
authors.initials: CM
authors.lastname: Tse
authors.affiliation: Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China. Electronic address: gphleung@hku.hk.
authors.forename: George Pak-Heng
authors.initials: GP
authors.lastname: Leung
mesh_terms: D001692:Biological Transport / Q000187:drug effects; D033721:Equilibrative Nucleoside Transporter 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D033722:Equilibrative-Nucleoside Transporter 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D009281:Naphthalenes / Q000737:chemistry / Q000494:pharmacology*; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D014227:Triazines / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C000616266:4-((4-(2-fluorophenyl)piperazin-1-yl)methyl)-6-imino-N-(naphthalen-2-yl)-1,3,5-triazin-2-amine; D033721:Equilibrative Nucleoside Transporter 1; D033722:Equilibrative-Nucleoside Transporter 2; D009281:Naphthalenes; D010879:Piperazines; C438649:SLC29A1 protein, human; C438654:SLC29A2 protein, human; D014227:Triazines
keywords: Cancer; Cardiovascular disease; Equilibrative nucleoside transporters; Inhibitor