新型吡啶并噻吩并嘧啶酮衍生物作为Pim-1抑制剂的合成

Synthesis of new pyridothienopyrimidinone derivatives as Pim-1 inhibitors.

作者信息

Naguib Bassem H, El-Nassan Hala B, Abdelghany Tamer M

机构信息

a Pharmaceutical Chemistry Department, Faculty of Pharmacy , The British University in Egypt , Cairo , Egypt.

b Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy , Cairo University , Cairo , Egypt.

出版信息

J Enzyme Inhib Med Chem. 2017 Dec;32(1):457-467. doi: 10.1080/14756366.2016.1261130.

Four series of pyridothienopyrimidin-4-one derivatives were designed and prepared to improve the pim-1 inhibitory activity of the previously reported thieno[2,3-b]pyridines. Significant improvement in the pim-1 inhibition and cytotoxic activity was achieved using structure rigidification strategy via ring closure. Six compounds (6c, 7a, 7c, 7d, 8b and 9) showed highly potent pim-1 inhibitory activity with IC of 4.62, 1.18, 1.38, 1.97, 8.83 and 4.18 μM, respectively. Four other compounds (6b, 6d, 7b and 8a) showed moderate pim-1 inhibition. The most active compounds were tested for their cytotoxic activity on three cell lines [MCF7, HCT116 and PC3]. Compounds 7a [the 2-(2-chlorophenyl)-2,3-dihydro derivative] and 7d [the 2-(2-(trifluoromethyl)-phenyl)-2,3-dihydro derivative] displayed the most potent cytotoxic effect on the three cell lines tested consistent with their highest estimated pim-1 IC values.

设计并制备了四类吡啶并噻吩并嘧啶-4-酮衍生物，以提高先前报道的噻吩并[2,3-b]吡啶的pim-1抑制活性。通过闭环的结构刚性化策略，pim-1抑制和细胞毒性活性得到了显著改善。六种化合物（6c、7a、7c、7d、8b和9）表现出高效的pim-1抑制活性，IC分别为4.62、1.18、1.38、1.97、8.83和4.18μM。另外四种化合物（6b、6d、7b和8a）表现出中等程度的pim-1抑制作用。对活性最强的化合物在三种细胞系[MCF7、HCT116和PC3]上进行了细胞毒性活性测试。化合物7a [2-(2-氯苯基)-2,3-二氢衍生物]和7d [2-(2-(三氟甲基)-苯基)-2,3-二氢衍生物]对所测试的三种细胞系表现出最强的细胞毒性作用，这与其最高的估计pim-1 IC值一致。