Design, Synthesis, and Biological Evaluation of Pyrazolo[3,4-d]pyrimidines Active in Vivo on the Bcr-Abl T315I Mutant
Design, Synthesis, and Biological Evaluation of Pyrazolo[3,4-d]pyrimidines Active in Vivo on the Bcr-Abl T315I Mutant
复制标题
DOI：
10.1021/jm400233w
复制
发表时间：
2013-07-11
影响因子：
7.3
通讯作者：
Botta, Maurizio
中科院分区：
文献类型：
--
作者：
Radi, Marco;Tintori, Cristina;Botta, Maurizio
从我们的吡唑并[3，4-d]嘧啶的内部文库开始，对Bcr-Abl T315 I突变体进行交叉对接模拟。在所选择的化合物（2a-e）中，4-溴衍生物2b显示出对Bcr-Abl T315 I突变体的最佳活性。更深入的计算研究强调了NI侧链苯环的对位溴原子对于与T315 I突变体相互作用的重要性。合成了一系列4;溴衍生物并进行了生物学评价。化合物2 j显示出不同ADME性质的良好平衡、在无细胞测定中的高活性和针对T315 IBcr-Abl表达细胞的亚微摩尔效力。此外，通过脂质体包封将其转化为水溶性制剂，保留了对白血病T315 I细胞的良好活性，并且避免使用DMSO作为增溶剂。对接种32 D-T315 I细胞并用2 j处理的小鼠的体内研究显示肿瘤体积减少超过50%。
Starting from our in-house library of pyrazolo, [3,4-d]pyrimidines, a cross-docking simulation was conducted, on Bcr-Abl T315I mutant. Among the selected, compounds; (2a-e), the 4-bromo derivative 2b showed the best activity against the Bcr-Abl T315I mutant. Deeper computational studies highlighted the importance of the bromine atom in the para position of the NI side chain phenyl,ring for the interaction with the T315I mutant. A series of 4;bromo derivatives was thin synthesized and biologically evaluated.: Compound 2j showed a good balance of different ADME properties, high activity in cell-free assays, and a submicromolar potency against T315I Bcr-Abl expressing cells. In addition, it was converted into a water-soluble formulation by liposome encapsulation, preserving a good activity on leukemic T315I cells and avoiding the use of DMSO as solubilizing agent. In vivo studies on mice inoculated with 32D-T315I cells and treated with 2j showed a more than 50% reduction in tumor volumes.