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

• Published in: Journal of medicinal chemistry Vol. 53; no. 16; pp. 6040 - 6053
• Main Authors: Robins, Morris J, Peng, Yunshan, Damaraju, Vijaya L, Mowles, Delores, Barron, Geraldine, Tackaberry, Tracey, Young, James D, Cass, Carol E
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 26-08-2010
• Subjects: Adenosine - analogs & derivatives; Adenosine - chemical synthesis; Adenosine - chemistry; Animals; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; Equilibrative Nucleoside Transporter 1 - chemistry; Equilibrative Nucleoside Transporter 1 - metabolism; Fluorescein-5-isothiocyanate - analogs & derivatives; Fluorescein-5-isothiocyanate - chemical synthesis; Fluorescein-5-isothiocyanate - chemistry; Fluorescent Dyes - chemical synthesis; Fluorescent Dyes - chemistry; Humans; Mice; Oocytes - metabolism; Protein Binding; Stereoisomerism; Structure-Activity Relationship; Thioinosine - analogs & derivatives; Thioinosine - pharmacology; Thionucleosides - chemical synthesis; Thionucleosides - chemistry; Xenopus; Yeasts - drug effects; Yeasts - metabolism
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm100432w

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 SNAr 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.