Pliva d.o.o., odjel TAPI I&R, Unapređenje tehnoloških procesa i Podrška proizvodnji, Croatia.
Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 19, HR-10000, Zagreb, Croatia.
Eur J Med Chem. 2021 May 5;217:113342. doi: 10.1016/j.ejmech.2021.113342. Epub 2021 Mar 3.
A novel series of tetracyclic imidazo[4,5-b]pyridine derivatives was designed and synthesized as potential antiproliferative agents. Their antiproliferative activity against human cancer cells was influenced by the introduction of chosen amino side chains on the different positions on the tetracyclic skeleton and particularly, by the position of N atom in the pyridine nuclei. Thus, the majority of compounds showed improved activity in comparison to standard drug etoposide. Several compounds showed pronounced cytostatic effect in the submicromolar range, especially on HCT116 and MCF-7 cancer cells. The obtained results have confirmed the significant impact of the position of N nitrogen in the pyridine ring on the enhancement of antiproliferative activity, especially for derivatives bearing amino side chains on position 2. Thus, regioisomers 6, 7 and 9 showed noticeable enhancement of activity in comparison to their counterparts 10, 11 and 13 with IC values in a nanomolar range of concentration (0.3-0.9 μM). Interactions with DNA (including G-quadruplex structure) and RNA were influenced by the position of amino side chains on the tetracyclic core of imidazo[4,5-b]pyridine derivatives and the ligand charge. Moderate to high binding affinities (logK = 5-7) obtained for selected imidazo[4,5-b]pyridine derivatives suggest that DNA/RNA are potential cell targets.
设计并合成了一系列新型四环咪唑并[4,5-b]吡啶衍生物，作为有潜力的抗增殖剂。它们对人癌细胞的抗增殖活性受到四环骨架上不同位置引入的所选氨基侧链的影响，特别是吡啶核中氮原子的位置。因此，大多数化合物与标准药物依托泊苷相比表现出更好的活性。一些化合物在亚微摩尔范围内表现出明显的细胞生长抑制作用，特别是对 HCT116 和 MCF-7 癌细胞。获得的结果证实了吡啶环中 N 氮位置对增强抗增殖活性的重要影响，特别是对于在 2 位带有氨基侧链的衍生物。因此，与在相同位置带有氨基侧链的 10、11 和 13 相比，6、7 和 9 这几个区域异构体的活性有显著提高，IC 值在纳摩尔浓度范围内（0.3-0.9 μM）。与 DNA（包括 G-四链体结构）和 RNA 的相互作用受到四环咪唑并[4,5-b]吡啶衍生物中环上氨基侧链的位置和配体电荷的影响。所选咪唑并[4,5-b]吡啶衍生物的结合亲和力适中至较高（logK=5-7），表明 DNA/RNA 是潜在的细胞靶标。
