Premium
8‐ BuS ‐ ATP derivatives as specific NTPD ase1 inhibitors
Author(s) -
Lecka Joanna,
Gillerman Irina,
Fausther Michel,
Salem Mabrouka,
Munkonda Mercedes N,
Brosseau JeanPhilippe,
Cadot Christine,
MartínSatué Mireia,
d'OrléansJuste Pedro,
Rousseau Éric,
Poirier Donald,
Künzli Beat,
Fischer Bilha,
Sévigny Jean
Publication year - 2013
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12135
Subject(s) - biochemistry , suramin , chemistry , nucleotide , enzyme , atp hydrolysis , adenosine diphosphate , adenine nucleotide , nucleoside , platelet , atpase , pharmacology , biology , in vitro , immunology , platelet aggregation , gene
Background and Purpose Ectonucleotidases control extracellular nucleotide levels and consequently, their (patho)physiological responses. Among these enzymes, nucleoside triphosphate diphosphohydrolase‐1 ( NTPD ase1), −2, −3 and −8 are the major ectonucleotidases responsible for nucleotide hydrolysis at the cell surface under physiological conditions, and NTPDa se1 is predominantly located at the surface of vascular endothelial cells and leukocytes. Efficacious inhibitors of NTPD ase1 are required to modulate responses induced by nucleotides in a number of pathological situations such as thrombosis, inflammation and cancer. Experimental Approach Here, we present the synthesis and enzymatic characterization of five 8‐ BuS ‐adenine nucleotide derivatives as potent and selective inhibitors of NTPD ase1. Key Results The compounds 8‐ BuS ‐ AMP , 8‐ BuS ‐ ADP and 8‐ BuS ‐ ATP inhibit recombinant human and mouse NTPD ase1 by mixed type inhibition, predominantly competitive with K i values <1 μ M . In contrast to 8‐ BuS ‐ ATP which could be hydrolyzed by other NTPD ases, the other BuS derivatives were resistant to hydrolysis by either NTPD ase1, −2, −3 or −8. 8‐ BuS ‐ AMP and 8‐ BuS ‐ ADP were the most potent and selective inhibitors of NTPD ase1 expressed in human umbilical vein endothelial cells as well as in situ in human and mouse tissues. As expected, as a result of their inhibition of recombinant human NTPD ase1, 8‐ BuS ‐ AMP and 8‐ BuS ‐ ADP impaired the ability of this enzyme to block platelet aggregation. Importantly, neither of these two inhibitors triggered platelet aggregation nor prevented ADP ‐induced platelet aggregation, in support of their inactivity towards P2Y 1 and P2Y 12 receptors. Conclusions and Implications The 8‐ BuS ‐ AMP and 8‐ BuS ‐ ADP have therefore potential to serve as drugs for the treatment of pathologies regulated by NTPD ase1.