Abstract：
A novel series of substituted thiazolo[5,4-b]pyridine analogues were rationally designed and synthesized via a multi-step synthetic pathway, including Suzuki cross-coupling reaction. The anticancer activity of all forty-five synthesized derivatives was evaluated against HCC827, H1975, and A549 cancer cell lines utilizing the standard MTT assay. A significant number of the thiazolo[5,4-b]pyridine derivatives exhibited potent anticancer activity. Notably, compounds 10b, 10c, 10h, 10i, and 10k emerged as the most promising anticancer agents. The lead compound, N-(3-(6-(2-aminopyrimidin-5-yl)thiazolo[5,4-b]pyridin-2-yl)-2-methylphenyl)-2,5-difluorobenzenesulfonamide (10k), displayed remarkable potency with IC50 values of 0.010 μM, 0.08 μM, and 0.82 μM against the HCC827, NCI-H1975 and A-549 cancer cell lines, respectively, which were comparable to the clinically approved drug Osimertinib. Importantly, the potent derivatives 10b, 10c, 10h, 10i, and 10k exhibited selective cytotoxicity towards cancer cells and showing no toxicity against the normal BEAS-2B cell line at concentrations exceeding 35 μM. Mechanistic studies revealed that the active compound 10k acts as an EGFR-TK autophosphorylation inhibitor in HCC827 cells. Furthermore, apoptosis assays demonstrated that compound 10k induced substantial early apoptosis (31.9 %) and late apoptosis (8.8 %) in cancer cells, in contrast to the control condition exhibiting only 2.0 % early and 1.6 % late apoptosis. Molecular docking simulations of the synthesized compounds revealed that they formed essential hinge interactions and established hydrogen bonding with Cys797, indicating potential target engagement. These findings highlight the potential of the synthesized thiazolo [(Woodburn, 1999; Zigrossi et al., 2022) 5,45,4-b]pyridine derivatives as promising anticancer agents, warranting further investigation for the development of novel targeted therapies against non-small cell lung cancer.
摘要：
通过多步合成途径合理设计合成了一系列取代的噻唑并[5,4-b]吡啶类似物,包括Suzuki交叉偶联反应。使用标准MTT测定法评估了所有45种合成衍生物对HCC827，H1975和A549癌细胞系的抗癌活性。大量的噻唑并[5,4-b]吡啶衍生物表现出有效的抗癌活性。值得注意的是,化合物10b,10c,10h,10i,10k成为最有前途的抗癌剂。铅化合物，N-(3-(6-(2-氨基嘧啶-5-基)噻唑并[5,4-b]吡啶-2-基)-2,5-二氟苯磺酰胺(10k),表现出显著的效力，IC50值为0.010μM，0.08μM,和0.82μM对HCC827，NCI-H1975和A-549癌细胞系，分别,与临床批准的药物奥希替尼相当。重要的是,有效的衍生物10b，10c,10h,10i,和10k表现出对癌细胞的选择性细胞毒性，并且在超过35μM的浓度下对正常BEAS-2B细胞系没有毒性。机制研究表明,活性化合物10k在HCC827细胞中充当EGFR-TK自磷酸化抑制剂。此外，凋亡试验表明，化合物10k在癌细胞中诱导大量早期凋亡(31.9%)和晚期凋亡(8.8%)，与对照条件相反，仅表现出2.0％的早期和1.6％的晚期凋亡。合成化合物的分子对接模拟表明，它们形成了必要的铰链相互作用，并与Cys797建立了氢键，表明了潜在的靶标接合。这些发现突出了合成噻唑的潜力[(伍德伯恩，1999；Zigrossi等人。,2022)5,45,4-b]吡啶衍生物作为有前途的抗癌剂，有必要进一步研究开发针对非小细胞肺癌的新型靶向疗法。
