Synthesis and flow cytometric evaluation of novel 1,2,3,4-tetrahydroisoquinoline conformationally constrained analogues of nitrobenzylmercaptopurine riboside (NBMPR) designed for probing its conformation when bound to the es nucleoside transporter.
Novel regioisomers of conformationally constrained analogues of the potent es nucleoside transporter ligand, nitrobenzylmercaptopurine riboside (NBMPR), designed for probing its bound (bioactive) conformation, were synthesized and evaluated as es transporter ligands by flow cytometry. Purine 6-position 5, 6, 7, or 8-nitro-1,2,3,4-tetrahydroisoquinolylpurine ribosides, in which the nitrobenzyl moiety in NBMPR has been locked into the nitro-1,2,3,4-tetrahydroisoquinoline system, were synthesized by reaction of the appropriate nitro-1,2,3,4-tetrahydroisoquinoline with 6-chloropurine riboside. Flow cytometry was performed using 5-(SAENTA)-X8-fluorescein as the competitive ligand. A high degree of variation in the es transporter binding capacity of the target compounds was observed, with the K(i) values ranging from 0.45 nM for the most tightly bound compound (4) to 300 nM for the least tightly bound compound (5). The K(i) of NBMPR was 0.70 nM, a little higher than that of compound 4. Compound 4 is the isomer that has the nitro group in the best orientation at the es transporter binding site compared to the other three compounds, 2, 3, and 5.
Zhu
Zhengxiang
Z
Department of Pharmaceutical Sciences, College of Pharmacy, 847 Monroe Avenue, Suite 327, University of Tennessee Health Sciences Center, Memphis, Tennessee 38163, USA.
Furr
John
J
Buolamwini
John K
JK
D033721:Equilibrative Nucleoside Transporter 1 / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009690:Nucleic Acid Conformation; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013868:Thioinosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D014407:Tumor Cells, Cultured
D033721:Equilibrative Nucleoside Transporter 1; D007546:Isoquinolines; D013868:Thioinosine; C001789:4-nitrobenzylthioinosine