Structural modifications at the 6-position of thieno[2,3-d]pyrimidines and their effects on potency at FLT3 for treatment of acute myeloid leukemia
Structural modifications at the 6-position of thieno[2,3-d]pyrimidines and their effects on potency at FLT3 for treatment of acute myeloid leukemia
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DOI：
10.1016/j.ejmech.2016.05.022
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发表时间：
2016-09-14
影响因子：
6.7
通讯作者：
Han, Gyoonhee
中科院分区：
文献类型：
--
作者：
Kim, Hyuntae;Lee, Chulho;Han, Gyoonhee
fms样酪氨酸激酶3 （FLT3）是治疗急性髓性白血病（AML）的一个众所周知的重要靶点。在6位上进行修饰，合成了一系列噻吩[2,3-d]嘧啶衍生物，以鉴定有效的FLT3抑制剂。虽然化合物1和2在合成的化合物中被认为是有前途的FLT3抑制剂，但这两种化合物在人和大鼠肝微粒体中表现出较差的代谢稳定性。因此，FLT3抑制剂的发现需要进一步优化，重点是改善代谢稳定性。化合物16d对5位的甲基和6位的4-（2-甲基氨基乙氧基）苯基进行了结构修饰，对FLT3具有良好的抑制活性，并对包括MV4-11在内的4种白血病细胞系显示出有效的抗增殖活性。此外，化合物16d显示出增强的代谢稳定性。本研究结果表明，作为一种有效的FLT3抑制剂，16d可能是一个有希望进一步优化和开发的化合物。(C) 2016 Elsevier Masson SAS。版权所有。
Fms-like tyrosine kinase 3 (FLT3) is a well-known and important target for the treatment of acute myeloid leukemia (AML). A series of thieno[2,3-d]pyrimidine derivatives from a modification at the 6 position were synthesized to identify effective FLT3 inhibitors. Although compounds 1 and 2 emerged as promising FLT3 inhibitors among the synthesized compounds, both compounds exhibited poor metabolic stability in human and rat liver microsomes. Hence, further optimization was required for the discovery of FLT3 inhibitors, with a focus on improving metabolic stability. Compound 16d, which had structural modifications of the methyl group at the 5-position and the 4-(2-methylaminoethoxy) phenyl group at the 6-position, exhibited good inhibitory activity against FLT3 and showed effective anti proliferative activity against four leukemia cell lines, including MV4-11. Moreover, compound 16d displayed enhanced metabolic stability. The results of this study indicated that 16d could be a promising compound for further optimization and development as a potent FLT3 inhibitor. (C) 2016 Elsevier Masson SAS. All rights reserved.