Pharmaceutical Chemistry Department, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt.
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt.
Bioorg Chem. 2018 Oct;80:674-692. doi: 10.1016/j.bioorg.2018.07.024. Epub 2018 Jul 21.
A series of pyridine and thieno[2,3-b]pyridine derivatives have been designed and synthesized as anticancer PIM-1 kinase inhibitors. Thirty-seven compounds were selected by NCI to be tested initially at a single dose (10 µM) in the full NCI 60 cell line panel. Compound 5b showed potent anticancer activity and was tested twice in the five-dose assay which confirmed its potent antitumor activity (GI values 0.302-3.57 µM) against all tested tumor cell lines except six cell lines where they showed moderate sensitivity. This compound was sent to NCI biological evaluation committee and still under consideration for further testing. In addition, the most active anticancer compounds in each series, 5b, 8d, 10c, 13h, and 15e, were evaluated for their PIM-1 kinase inhibitory activity. Compound 8d was the most potent one with IC = 0.019 µM followed by 5b, 15e, 10c and 13h with IC values 0.044, 0.083, 0.128 and 0.479 µM respectively. Moreover, docking study of the most active compounds in PIM-1 kinase active site was consistent with the in vitro activity.
已经设计和合成了一系列吡啶和噻吩并[2,3-b]吡啶衍生物作为抗癌 PIM-1 激酶抑制剂。选择了 37 种化合物由 NCI 进行测试，最初在 NCI 60 细胞系面板中以单剂量（10µM）进行测试。化合物 5b 表现出很强的抗癌活性，并在五剂量测定中进行了两次测试，证实了其对所有测试的肿瘤细胞系（除了六种细胞系，它们表现出中等敏感性）的强烈抗肿瘤活性（GI 值为 0.302-3.57µM）。该化合物已提交给 NCI 生物评估委员会，仍在考虑进一步测试。此外，对每个系列中最活跃的抗癌化合物 5b、8d、10c、13h 和 15e 进行了 PIM-1 激酶抑制活性评估。化合物 8d 的抑制活性最强，IC50 值为 0.019µM，其次是 5b、15e、10c 和 13h，IC50 值分别为 0.044µM、0.083µM、0.128µM 和 0.479µM。此外，在 PIM-1 激酶活性位点中最活跃的化合物的对接研究与体外活性一致。
