부산대학교 도서관

ecto-5′-Nucleotidase (eN, CD73)catalyzes the hydrolysis of extracellular AMP to adenosine. eN inhibitors have potential for use as cancer therapeutics.The eN inhibitor α,β-methylene-ADP (AOPCP,adenosine-5′-O-[(phosphonomethyl)phosphonicacid]) was used as a lead structure, and derivatives modified in variouspositions were prepared. Products were tested at rat recombinant eN. 6-(Ar)alkylamino substitution led to the largest improvementin potency. N6-Monosubstitution was superiorto symmetrical N6,N6-disubstitution. The most potent inhibitors were N6-(4-chlorobenzyl)- (10l, PSB-12441, Ki7.23 nM), N6-phenylethyl-(10h, PSB-12425, Ki8.04nM), and N6-benzyl-adenosine-5′-O-[(phosphonomethyl)phosphonic acid] (10g,PSB-12379, Ki9.03 nM). Replacement ofthe 6-NH group in 10gby O (10q, PSB-12431)or S (10r, PSB-12553) yielded equally potent inhibitors(10q, 9.20 nM; 10r, 9.50 nM). Selected compoundsinvestigated at the human enzyme did not show species differences;they displayed high selectivity versus other ecto-nucleotidases and ADP-activated P2Y receptors. Moreover, high metabolicstability was observed. These compounds represent the most potent eN inhibitors described to date. [ABSTRACT FROM AUTHOR]