Abstract:
:Adenosine induces glioma cell proliferation by means of an antiapoptotic effect, which is blocked by cotreatment with selective A(3) AR antagonists. In this study, a novel series of N(2)-substituted pyrazolo[3,4-d]pyrimidines 2a-u was developed as highly potent and selective A(3) AR antagonists. The most performing compounds were derivatives 2a (R(1) = CH(3) and R(2) = COC(6)H(5); K(i) 334, 728, and 0.60 nM at the human A(1), A(2A), and A(3) ARs, respectively) and 2b (R(1) = CH(3) and R(2) = COC(6)H(4)-4-OCH(3); K(i) 1037, 3179, and 0.18 nM at the human A(1), A(2A), and A(3) ARs, respectively), which counteracted the effect of the A(3) AR agonists Cl-IB-MECA and IB-MECA on human glioma U87MG cell proliferation. This effect was concentration-dependent, with IC(50) values comparable to A(3) AR binding affinity values of 2a and 2b, thereby suggesting that their effects were receptor-mediated. Furthermore, the antiproliferative activity of the new compounds was demonstrated to be mediated by the block of A(3) AR agonist activation of intracellular kinases ERK 1/2.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Taliani S,La Motta C,Mugnaini L,Simorini F,Salerno S,Marini AM,Da Settimo F,Cosconati S,Cosimelli B,Greco G,Limongelli V,Marinelli L,Novellino E,Ciampi O,Daniele S,Trincavelli ML,Martini Cdoi
10.1021/jm901785wsubject
Has Abstractpub_date
2010-05-27 00:00:00pages
3954-63issue
10eissn
0022-2623issn
1520-4804journal_volume
53pub_type
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