Department of Chemistry, Radhabai Kale Mahila Mahavidyalay, Ahmednagar, Maharashtra, 414001, India.
Department of Chemistry, Ahmednagar College, Ahmednagar, Maharashtra, 414001, India.
Eur J Med Chem. 2024 Oct 5;276:116727. doi: 10.1016/j.ejmech.2024.116727. Epub 2024 Jul 30.
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 IC 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.
通过多步合成途径，包括 Suzuki 交叉偶联反应，合理设计并合成了一系列新型取代噻唑并[5,4-b]吡啶类似物。利用标准 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。大量噻唑并[5,4-b]吡啶衍生物表现出很强的抗癌活性。值得注意的是，化合物 10b、10c、10h、10i 和 10k 是最有前途的抗癌剂。先导化合物 N-(3-(6-(2-氨基嘧啶-5-基)噻唑并[5,4-b]吡啶-2-基)-2-甲基苯基)-2,5-二氟苯磺酰胺（10k）对 HCC827、NCI-H1975 和 A-549 癌细胞系的 IC 值分别为 0.010 μM、0.08 μM 和 0.82 μM，与临床批准药物奥希替尼相当。重要的是，强效衍生物 10b、10c、10h、10i 和 10k 对癌细胞表现出选择性细胞毒性，并且在浓度超过 35 μM 时对正常 BEAS-2B 细胞系没有毒性。机制研究表明，活性化合物 10k 作为一种 EGFR-TK 自动磷酸化抑制剂在 HCC827 细胞中发挥作用。此外，凋亡实验表明，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%），而对照条件仅显示 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，它们与 Cys797 形成了必需的铰链相互作用并建立了氢键，表明潜在的靶标结合。这些发现突出了合成的噻唑并[5,4-b]吡啶衍生物作为有前途的抗癌剂的潜力，值得进一步研究，以开发针对非小细胞肺癌的新型靶向治疗方法。
