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.
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.
Robins
Morris J
MJ
Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah 84602-5700, USA. morris_robins@byu.edu
Peng
Yunshan
Y
Damaraju
Vijaya L
VL
Mowles
Delores
D
Barron
Geraldine
G
Tackaberry
Tracey
T
Young
James D
JD
Cass
Carol E
CE
D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D033721:Equilibrative Nucleoside Transporter 1 / Q000737:chemistry / Q000378:metabolism*; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D005456:Fluorescent Dyes / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D051379:Mice; D009865:Oocytes / Q000378:metabolism; D011485:Protein Binding; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013868:Thioinosine / Q000031:analogs & derivatives / Q000494:pharmacology; D013872:Thionucleosides / Q000138:chemical synthesis* / Q000737:chemistry; D014981:Xenopus; D015003:Yeasts / Q000187:drug effects / Q000378:metabolism; D000093542:Gemcitabine
D000970:Antineoplastic Agents; D033721:Equilibrative Nucleoside Transporter 1; D005456:Fluorescent Dyes; C438649:SLC29A1 protein, human; D013872:Thionucleosides; D003841:Deoxycytidine; C066257:5'-S-(2-aminoethyl)-N(6)-(4-nitrobenzyl)-5'-thioadenosine; D013868:Thioinosine; C001789:4-nitrobenzylthioinosine; D016650:Fluorescein-5-isothiocyanate; D000241:Adenosine; D000093542:Gemcitabine