A series of 28 novel cabotegravir derivatives, incorporating the 1,2,3-triazole moiety, were designed and synthesized. The synthesized compounds were evaluated for their potential anticancer activity against four different human cancer cell lines: HuH-7 (hepatocellular), MCF-7 (breast), SKOV3 (ovarian), and HCT-116 (colon). Initial biological assessments revealed that several compounds exhibited potent anti-proliferative activity against these cancer cell lines. Notably, compounds KJ9 and KJ23 demonstrated the most pronounced effects, with IC values of 6.59 and 7.83μM in HuH-7 cells, 27.24 and 8.59μM in MCF-7 cells, 4.46 and 6.30μM in SKOV3 cells, 23.90 and 17.00μM in HCT-116 cells, respectively. Further investigations demonstrated that compound KJ9 and KJ23 induced cell apoptosis, elevated reactive oxygen species (ROS) levels, and ultimately led to cell death. Additionally, western blot analysis revealed altered expressions of proteins involved in autophagy and DNA damage following treatment with compound KJ9 and KJ23. Molecular structure analysis found that the novel compounds tend towards a planar conformation which contained multiple rigid planar structures. This planar structure makes it possible for the compounds to intercalate into DNA and causing DNA damage. These findings suggested that cabotegravir-1,2,3-triazole derivatives possess potential antitumor abilities and warrant further investigations for the development of novel anticancer drugs.

中文翻译：

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具有有效抗癌活性的新型 1,2,3-三唑卡博特韦衍生物的合成和发现

设计并合成了一系列 28 种新型卡博特韦衍生物，其中包含 1,2,3-三唑部分。评估了合成化合物对四种不同人类癌细胞系的潜在抗癌活性：HuH-7（肝细胞）、MCF-7（乳腺癌）、SKOV3（卵巢）和 HCT-116（结肠）。初步的生物学评估表明，几种化合物对这些癌细胞系表现出有效的抗增殖活性。值得注意的是，化合物 KJ9 和 KJ23 表现出最显着的作用，在 HuH-7 细胞中的 IC 值分别为 6.59 和 7.83μM，在 MCF-7 细胞中为 27.24 和 8.59μM，在 SKOV3 细胞中为 4.46 和 6.30μM，在 HCT 中为 23.90 和 17.00μM分别为-116个细胞。进一步的研究表明，化合物 KJ9 和 KJ23 诱导细胞凋亡，升高活性氧 (ROS) 水平，并最终导致细胞死亡。此外，蛋白质印迹分析显示，用化合物 KJ9 和 KJ23 处理后，参与自噬和 DNA 损伤的蛋白质表达发生改变。分子结构分析发现，新型化合物倾向于包含多个刚性平面结构的平面构象。这种平面结构使得化合物能够嵌入 DNA 并造成 DNA 损伤。这些发现表明，cabotegravir-1,2,3-三唑衍生物具有潜在的抗肿瘤能力，值得进一步研究以开发新型抗癌药物。