title: Inhibition of nucleoside transport by new analogues of nitrobenzylthioinosine.
abstract: Nitrobenzylthioinosine (NBTI, 1) was systematically modified by attachment of substituents at positions C6 and N9, and also by substitution of N1 with C. These modifications were chosen to reduce the polarity of the new compounds. Incorporation of the nitro functionality into a benzoxadiazole ring system was considered first. These new nucleosides showed high affinity (1.5-10nM) towards the nucleoside transport protein as present on human erythrocyte ghosts. Next, modification of this benzoxadiazole ring system with C, S and O in different positions produced a number of less polar nucleosides with affinity in the higher nanomolar range. Modification of N9 was achieved with different alkyl and alcohol substituents. An n-butyl substituent proved best, although all variations yielded substantial decreases in affinity. Replacement of N1 by a carbon atom in combination with a 2-Cl substituent also resulted in a relatively potent NBTI derivative (47 nM).
authors.affiliation: Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, University of Leiden, PO Box 9502, 2300RA Leiden, The Netherlands.
authors.forename: Paymaneh Y F
authors.initials: PY
authors.lastname: Deghati
authors.forename: Alice
authors.initials: A
authors.lastname: Borghini
authors.forename: Adrianus M C H
authors.initials: AM
authors.lastname: van den Nieuwendijk
authors.forename: Miriam
authors.initials: M
authors.lastname: Dissen-de Groote
authors.forename: Adriaan P
authors.initials: AP
authors.lastname: IJzerman
mesh_terms: D000478:Alkylation; D001693:Biological Transport, Active / Q000187:drug effects; D004910:Erythrocyte Membrane / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D009705:Nucleosides / Q000378:metabolism*; D011869:Radioligand Assay; D013329:Structure-Activity Relationship; D013868:Thioinosine / Q000031:analogs & derivatives* / Q000494:pharmacology*
chemical_list: D007202:Indicators and Reagents; D009705:Nucleosides; D013868:Thioinosine; C001789:4-nitrobenzylthioinosine