Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland.
Department für Chemie, Institut für Biochemie, Universtät zu Köln, Zülpicher Straße 47, D-50674 Köln, Germany.
Bioorg Chem. 2018 Oct;80:266-275. doi: 10.1016/j.bioorg.2018.06.022. Epub 2018 Jun 22.
The new aminoalkyl-substituted derivatives of known CK2 inhibitors 4,5,6,7-tetrabromo-1H-benzimidazole (TBBi) and 4,5,6,7-tetrabromo-1H-benzotriazole (TBBt) were synthesized, and their influence on the activity of recombinant human CK2 α, CK2 holoenzyme and PIM1 kinases was evaluated. All derivatives inhibited the activity of studied kinases and the most efficient were aminopropyl-derivatives 8b and 14b. These compounds also exerted inhibition of cancer cell lines - CCRF-CEM (acute lymphoblastoid leukemia), MCF-7 (human breast cancer), and PC-3 (prostate cancer) proliferation and their EC is comparable with the value for clinically studied CK2 inhibitor CX-4945. Preliminary structure activity relationship analysis indicated that the spacer length affected antitumor potency, and two to three methylene units were more favorable. The complex of CK2 α/8b was crystallized, both under high-salt conditions and under low-salt conditions giving crystals which diffracted X-rays to about 2.4 Å resolution, what enabled the determination of the corresponding 3D-structures.
合成了已知 CK2 抑制剂 4,5,6,7-四溴-1H-苯并咪唑（TBBi）和 4,5,6,7-四溴-1H-苯并三唑（TBBt）的新的氨烷基取代衍生物，并评估了它们对重组人 CK2α、CK2 全酶和 PIM1 激酶活性的影响。所有衍生物均抑制了研究激酶的活性，其中最有效的是氨丙基衍生物 8b 和 14b。这些化合物还抑制了癌细胞系 - CCRF-CEM（急性淋巴细胞白血病）、MCF-7（人乳腺癌）和 PC-3（前列腺癌）的增殖，其 EC 与临床研究的 CK2 抑制剂 CX-4945 的值相当。初步的结构活性关系分析表明，间隔基长度影响抗肿瘤效力，两个到三个亚甲基单元更为有利。CK2α/8b 的复合物进行了结晶，在高盐条件和低盐条件下都得到了能够衍射 X 射线至约 2.4 Å 分辨率的晶体，这使得相应的 3D 结构得以确定。
