Inhibition of nucleoside transport proteins by C8-alkylamine-substituted purines.
4-nitrobenzylthioinosine (NBTI, 1) is a well-known inhibitor for the nucleoside transport protein ENT1. Here we report on the synthesis and the biological evaluation of compounds that are less polar than NBTI. Compound screening in our laboratory indicated that introduction of an alkylamine substituent at the C(8)-position of N(6)-cyclopentyladenosine (CPA, 2) led to an increment in affinity for the transport protein. It was investigated whether this would also apply for NBTI derivatives. Two series of C(8)-alkylamine-substituted compounds were prepared, one in which the nitro group was absent (46-58) and another in which the ribose moiety was replaced by a benzyl group (72-75). Comparison of the biological data of these compounds with 6-benzylthioinosine (4, K(i) = 53 nM) and 9-benzyl-6-(4-nitrobenzylsulfanyl)purine (59, K(i) = 135 nM) confirmed the hypothesis. The K(i) values improved upon elongation of the alkylamine chain from methylamine to n-hexylamine with an optimum for n-pentylamine (50, K(i) = 2.3 nM). Substitution with 2-methylbutylamine (52), cyclopropylamine (53), cyclopentylamine (54, 72), and cyclohexylamine (55, 73) revealed that the presence of a bulky group enhanced the affinity. The presence of tertiary amines obtained by substitution with pyrrolidine, piperidine, and morpholine gave only poor results. For both series substitution with cyclopentylamine was most effective. Compound 54 (LUF5942) proved the most active, showing a comparable affinity (K(i) = 0.64 nM) to NBTI but a significantly lower polar surface area.
Tromp
Reynier A
RA
Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, Leiden University, P.O. Box 9502, 2300RA Leiden, The Netherlands.
Spanjersberg
Ronald F
RF
von Frijtag Drabbe Künzel
Jacobien K
JK
IJzerman
Adriaan P
AP
D000588:Amines / Q000737:chemistry; D000818:Animals; D001671:Biochemistry / Q000379:methods; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D004353:Drug Evaluation, Preclinical / Q000379:methods; D033721:Equilibrative Nucleoside Transporter 1 / Q000037:antagonists & inhibitors; D004910:Erythrocyte Membrane / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D033703:Nucleoside Transport Proteins / Q000037:antagonists & inhibitors*; D011687:Purines / Q000737:chemistry* / Q000494:pharmacology*; D043682:Receptor, Adenosine A1 / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D013868:Thioinosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
D000588:Amines; D033721:Equilibrative Nucleoside Transporter 1; D033703:Nucleoside Transport Proteins; D011687:Purines; D043682:Receptor, Adenosine A1; C438649:SLC29A1 protein, human; D013868:Thioinosine; C001789:4-nitrobenzylthioinosine