Diadenosine and diuridine poly(borano)phosphate analogues: synthesis, chemical and enzymatic stability, and activity at P2Y1 and P2Y2 receptors.
Dinucleoside polyphosphates, NpnN', exert their physiological effects via P2 receptors. They are attractive drug targets as they offer better stability and specificity compared to nucleotides, the most common P2-receptor ligands. To further improve the properties of NpnN', which are still pharmacologically unsatisfactory, we developed novel boranophosphate isosteres of dinucleoside polyphosphates, denoted as Npn(B)N. These analogues were obtained in a facile and efficient synthesis as the exclusive products in a concerted reaction of two nucleoside phosphorimidazolides and inorganic boranophosphate. This unusual reaction is due to the preorganization of three reactant molecules by the Mg2+ ion. We found that Ap3/5(beta/gamma-B)A analogues were potent P2Y1-R agonists. Ap5(gamma-B)A was equipotent to 2-MeS-ADP (EC50 6.3x10(-8) M), thus making it one of the most potent P2Y1-R agonists currently known. Moreover, Ap5(gamma-B)A did not activate P2Y2-R. In contrast, Up3/5(beta/gamma-B)U analogues were extremely poor agonists of both P2Y1-R and P2Y2-R. Npn(B)N analogues exhibited remarkable chemical stability under physiological conditions. Under conditions mimicking gastric juice, Np3(beta-B)N analogues exhibited a half-life (t1/2) of 1.3 h, whereas Np5(gamma-B)N degraded at a much faster rate (t1/2 18 min). The hydrolysis of Ap3(beta-B)A by human nucleotide pyrophosphatase phosphodiesterases (NPP1 and NPP3) was slowed by 40% and 59%, respectively, as compared to Ap3A. However, this effect of the boranophosphate was position-dependent, as Np5(gamma-B)N was degraded at a rate comparable to that of Np5N. In summary, Ap5(gamma-B)A appears to be a highly potent and selective P2Y1-R agonist, as compared to the parent compound. This promising scaffold will be applied in the design of future metabolically stable analogues.
Department of Chemistry, Gonda-Goldschmied Medical Research Center, Bar-Ilan University, Ramat-Gan 52900, Israel.
Victoria
V
Nahum
Mohan
M
Tulapurkar
Sébastien A
SA
Lévesque
Jean
J
Sévigny
Georg
G
Reiser
Bilha
B
Fischer
D000241:Adenosine / Q000737:chemistry; D000818:Animals; D001880:Boranes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002522:Chlorocebus aethiops; D018360:Crystallography, X-Ray; D015226:Dinucleoside Phosphates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004355:Drug Stability; D006801:Humans; D006868:Hydrolysis; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry*; D058910:Purinergic P2 Receptor Agonists; D011755:Pyrophosphatases / Q000737:chemistry*; D051381:Rats; D058472:Receptors, Purinergic P2Y1; D058473:Receptors, Purinergic P2Y2; D014529:Uridine / Q000737:chemistry
D001880:Boranes; D015226:Dinucleoside Phosphates; C427944:ENPP3 protein, human; C546382:P2RY1 protein, human; C546385:P2RY2 protein, human; D058910:Purinergic P2 Receptor Agonists; D058472:Receptors, Purinergic P2Y1; D058473:Receptors, Purinergic P2Y2; D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D011755:Pyrophosphatases; D000241:Adenosine; D014529:Uridine