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Improved syntheses of 5'-S-(2-aminoethyl)-6-N-(4-nitrobenzyl)-5'-thioadenosine (SAENTA), analogues, and fluorescent probe conjugates: analysis of cell-surface human equilibrative nucleoside transporter 1 (hENT1) levels for prediction of the antitumor efficacy of gemcitabine.

Abstract
5'-S-(2-aminoethyl)-6-N-(4-nitrobenzyl)-5'-thioadenosine (SAENTA), 5'-S-(2-acetamidoethyl)-6-N-[(4-substituted)benzyl]-5'-thioadenosine analogues, 5'-S-[2-(6-aminohexanamido)]ethyl-6-N-(4-nitrobenzyl)-5'-thioadenosine (SAHENTA), and related compounds were synthesized by S(N)Ar displacement of fluoride from 6-fluoropurine intermediates with 4-(substituted)benzylamines. Conjugation of the pendant amino groups of SAENTA and SAHENTA with fluorescein-5-yl isothiocyanate (FITC) gave fluorescent probes that bound at nanomolar concentrations specifically to human equilibrative nucleoside transporter 1 (hENT1) produced in recombinant form in model expression systems and in native form in cancer cell lines. Transporter binding effects were studied and the ability of the probes to predict the potential antitumor efficacy of 2'-deoxy-2',2'-difluorocytidine (gemcitabine) was demonstrated.
AuthorsMorris J Robins, Yunshan Peng, Vijaya L Damaraju, Delores Mowles, Geraldine Barron, Tracey Tackaberry, James D Young, Carol E Cass
JournalJournal of medicinal chemistry (J Med Chem) Vol. 53 Issue 16 Pg. 6040-53 (Aug 26 2010) ISSN: 1520-4804 [Electronic] United States
PMID20718495 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • Equilibrative Nucleoside Transporter 1
  • Fluorescent Dyes
  • SLC29A1 protein, human
  • Thionucleosides
  • Deoxycytidine
  • 5'-S-(2-aminoethyl)-N(6)-(4-nitrobenzyl)-5'-thioadenosine
  • 4-nitrobenzylthioinosine
  • Thioinosine
  • gemcitabine
  • Fluorescein-5-isothiocyanate
  • Adenosine
Topics
  • Adenosine (analogs & derivatives, chemical synthesis, chemistry)
  • Animals
  • Antineoplastic Agents (pharmacology)
  • Cell Line, Tumor
  • Deoxycytidine (analogs & derivatives, pharmacology)
  • Equilibrative Nucleoside Transporter 1 (chemistry, metabolism)
  • Fluorescein-5-isothiocyanate (analogs & derivatives, chemical synthesis, chemistry)
  • Fluorescent Dyes (chemical synthesis, chemistry)
  • Humans
  • Mice
  • Oocytes (metabolism)
  • Protein Binding
  • Stereoisomerism
  • Structure-Activity Relationship
  • Thioinosine (analogs & derivatives, pharmacology)
  • Thionucleosides (chemical synthesis, chemistry)
  • Xenopus
  • Yeasts (drug effects, metabolism)

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