Tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide) is an inhibitor of inosine monophosphate dehydrogenase (IMPDH) endowed with antitumor activity. Phase I and phase II clinical studies are under way to evaluate its therapeutic potential. These studies pointed out that human recipients of intravenous tiazofurin frequently complain of headaches as well as displaying personality changes and obtundation. It was hypothized that the tiazole ring of tiazofurin enables the drug to interact with the adenosine receptors of the central nervous system. On the basis of binding studies we ascertained that tiazofurin is able to bind selectively to A1 adenosine receptors (bovine cortical membranes), albeit with moderate affinity (Ki = 1.6 x 10-3 M). This affinity was unrelated to IMPDH inhibition because the oxazole analogue of tiazofurin (oxazofurin), a C-nucleoside unable to inhibit the enzyme, proved to be more active than tiazofurin as agonist of A1 adenosine receptors (Ki = 2.4 x 10-4 M). Recently, we synthesized furanfurin, the furan analogue of oxazofurin, which in binding studies showed an affinity for A1 adenosine receptor higher than that of the parent compound (Ki = 5.9 x 10-5 M). The present communication describes the synthesis of furanfurin derivatives which were tested in binding and adenylate cyclase assays to evaluate their potency ot A1 adenosine receptors. In binding studies the most active compound was found to be 2-beta-D-ribofurasylfuran-4-carboxylic acid (Ki = 3.4 x 10-5 M). These results pointed out that the nitrogen atom in the heterocyclic rings of tiazofurin and oxazofurin is not involved in the binding at A1 adenosine receptors.

C-Nucleosides analogues of oxazofurin as selective agonists for adenosine A1 receptors

CAPPELLACCI, Loredana;GRIFANTINI, Mario;
1998

Abstract

Tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide) is an inhibitor of inosine monophosphate dehydrogenase (IMPDH) endowed with antitumor activity. Phase I and phase II clinical studies are under way to evaluate its therapeutic potential. These studies pointed out that human recipients of intravenous tiazofurin frequently complain of headaches as well as displaying personality changes and obtundation. It was hypothized that the tiazole ring of tiazofurin enables the drug to interact with the adenosine receptors of the central nervous system. On the basis of binding studies we ascertained that tiazofurin is able to bind selectively to A1 adenosine receptors (bovine cortical membranes), albeit with moderate affinity (Ki = 1.6 x 10-3 M). This affinity was unrelated to IMPDH inhibition because the oxazole analogue of tiazofurin (oxazofurin), a C-nucleoside unable to inhibit the enzyme, proved to be more active than tiazofurin as agonist of A1 adenosine receptors (Ki = 2.4 x 10-4 M). Recently, we synthesized furanfurin, the furan analogue of oxazofurin, which in binding studies showed an affinity for A1 adenosine receptor higher than that of the parent compound (Ki = 5.9 x 10-5 M). The present communication describes the synthesis of furanfurin derivatives which were tested in binding and adenylate cyclase assays to evaluate their potency ot A1 adenosine receptors. In binding studies the most active compound was found to be 2-beta-D-ribofurasylfuran-4-carboxylic acid (Ki = 3.4 x 10-5 M). These results pointed out that the nitrogen atom in the heterocyclic rings of tiazofurin and oxazofurin is not involved in the binding at A1 adenosine receptors.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11581/242232
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