Inhibition of Nucleoside Transport Proteins by C⁸-Alkylamine-Substituted Purines

Abstract

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.

The Antiepileptic Potential of Nucleosides

“…Modifications of NBTI, including LUF5942, were found to be potent inhibitors with lowered polar surface area [331]. The most potent and selective inhibitor of ENT1 is nitrobenzylmercaptopurine riboside (NBMPR) (Fig.…”

Production, Characterization and Synthetic Application of a Purine Nucleoside Phosphorylase from Aeromonas hydrophila

“…[40] and purified by flash chromatography, eluent: CH 2 Cl 2 /MeOH = 7/1; yield: 95%. 8-(Ethanolamino)inosine (1i): To a solution of 2',3',5'-Otriacetyl-8-bromoinosine [39] (100 mg, 0.21 mmol) in dry dioxane (1 mL) was added ethanolamine (180 mL, 2.94 mmol) under an N 2 atmosphere, and the mixture was stirred at 80 8C while monitoring the reaction progress by TLC (CH 2 Cl 2 /MeOH = 7/2).…”

Adenosine protects against suicidal erythrocyte death

“…Our attempts to inhibit cellular uptake of adenosine by inhibition of the nucleoside transporter with NBMPR [20,42,58,85] or to abrogate stimulation of purinergic receptors utilizing the unspecific purinergic receptor antagonist CGS-15943 [20,42,58,79,85], the adenosine A1-receptor antagonist FSCPX [80], or the adenosine A3 receptor antagonist VUF5574 [61] failed to reverse the inhibitory effect of adenosine on phosphatidylserine exposure. This observation does not rule out, although, that cellular adenosine uptake or activation of receptors by adenosine contributes to or even accounts for the antieryptotic effect of adenosine.…”

“…Removal of Cl − leads to exit of KCl and osmotically obliged water and thus to cell shrinkage, a well-known trigger of eryptosis [45]. Adenosine was used at concentrations ranging from 10 to 100 μM, the nucleoside transport inhibitor S-(4-Nitrobenzyl)-6-thioinosine (NBMPR) [20,42,58,85] …”