Dipartimento di Scienze Farmaceutiche, Università di Pisa, Pisa, Italy.
J Med Chem. 2010 May 27;53(10):3954-63. doi: 10.1021/jm901785w.
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.
腺嘌呤通过抗细胞凋亡作用诱导神经胶质瘤细胞增殖,这种作用可被选择性 A(3)AR 拮抗剂的共同处理所阻断。在这项研究中,开发了一系列新型的 N(2)-取代的吡唑并[3,4-d]嘧啶 2a-u 作为高活性和选择性的 A(3)AR 拮抗剂。表现最出色的化合物是衍生物 2a(R(1) = CH(3) 和 R(2) = COC(6)H(5);在人 A(1)、A(2A)和 A(3)AR 上的 K(i)分别为 334、728 和 0.60 nM)和 2b(R(1) = CH(3) 和 R(2) = COC(6)H(4)-4-OCH(3);在人 A(1)、A(2A)和 A(3)AR 上的 K(i)分别为 1037、3179 和 0.18 nM),它们能拮抗 A(3)AR 激动剂 Cl-IB-MECA 和 IB-MECA 对人神经胶质瘤 U87MG 细胞增殖的作用。这种作用呈浓度依赖性,IC(50)值与 2a 和 2b 的 A(3)AR 结合亲和力值相当,表明其作用是受体介导的。此外,新化合物的抗增殖活性被证明是通过阻断 A(3)AR 激动剂激活细胞内激酶 ERK 1/2 介导的。