Inhibition of nucleoside transport by new analogues of 4-nitrobenzylthioinosine: replacement of the ribose moiety by substituted benzyl groups.
4-Nitrobenzylthioinosine (NBTI, 1) is a well-known inhibitor for the nucleoside transport protein ENT1. However, its highly polar nature is unfavorable for oral absorption and/or penetration into the CNS. In the search for compounds with lower polarity than NBTI we replaced its ribose moiety by substituted benzyl groups. Halogen, hydroxyl, (trifluoro)methyl(-oxy), nitro, and amine functionalities were among the substituents at the benzyl group. In general, substitution of the benzyl group resulted in a lower affinity for ENT1. Only 2-hydroxyl substitution showed a higher affinity. Most likely this is the result of hydrogen bonding. Substitution at the 2-position of the benzyl group with aryl groups was also addressed. Compared to parent compound carrying a 2-phenylbenzyl group, all synthesized analogues gave higher affinities. Introduction of fluoro, trifluoromethyl, methoxy, and hydroxyl groups at the phenyl group clearly showed that addition to the 4-position was preferable. Despite the highly different character of a ribose and a benzyl group, Ki values in the low nanomolar range were obtained for the benzyl-substituted derivatives. Compound 35, LUF5919, and compound 60, LUF5929, displayed the highest affinity (Ki = 39 nM for both compounds), having a polar surface area of 101 A2 and 85 A2, respectively.
Tromp
Reynier A
RA
Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, Leiden University, P.O. Box 9502, 2300RA Leiden, The Netherlands.
van Ameijde
Susan
S
Pütz
Claudia
C
Sundermann
Corinna
C
Sundermann
Bernd
B
von Frijtag Drabbe Künzel
Jacobien K
JK
IJzerman
Adriaan P
AP
D001692:Biological Transport / Q000187:drug effects; D018360:Crystallography, X-Ray; D033721:Equilibrative Nucleoside Transporter 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004910:Erythrocyte Membrane / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008958:Models, Molecular; D009578:Nitrobenzenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011687:Purines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D013329:Structure-Activity Relationship; D013873:Thionucleotides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C493520:6-(4-nitrobenzylsulfanyl)-9-(4'-trifluoromethylbiphenyl-2-ylmethyl)purine; C493519:9-(2-hydroxybenzyl)-6-(4-nitrobenzylsulfanyl)purine; D033721:Equilibrative Nucleoside Transporter 1; D009578:Nitrobenzenes; D011687:Purines; D013873:Thionucleotides