Chemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt.
Department of Physics and Chemistry, Faculty of Education, Alexandria University, Alexandria, Egypt.
J Enzyme Inhib Med Chem. 2024 Dec;39(1):2423174. doi: 10.1080/14756366.2024.2423174. Epub 2024 Nov 8.
A series of triazole-tethered triazines bearing pharmacophoric features of DNA-targeting agents and non-hydroxamate MMPs inhibitors were synthesized and screened against HCT-116, Caco-2 cells, and normal colonocytes by MTT assay. and surpassed doxorubicin against HCT-116 cells regarding potency (IC = 0.87 and 1.41 nM) and safety (SI = 181.93 and 54.41). was potent against liver cancer (HepG-2; IC = 65.08 nM), the main metastatic site of CRC with correlation to MMP-13 expression. Both derivatives induced DNA damage at 2.67 and 1.87 nM, disrupted HCT-116 cell cycle and triggered apoptosis by 33.17% compared to doxorubicin (DNA damage at 0.76 nM and 40.21% apoptosis induction). surpassed NNGH against MMP-10 (IC = 0.205 μM) and MMP-13 (IC = 0.275 μM) and downregulated HCT-116 VEGF related to CRC progression by 38%. Docking and MDs simulated ligands-receptors binding modes and highlighted SAR. Their ADMET profiles, drug-likeness and possible off-targets were computationally predicted.
一系列含有 DNA 靶向药物和非羟肟酸基质金属蛋白酶抑制剂特征的三唑键合三嗪类化合物被合成，并通过 MTT 分析在 HCT-116、Caco-2 细胞和正常结肠细胞中进行筛选。与多柔比星相比， 对 HCT-116 细胞的活性（IC = 0.87 和 1.41 nM）和安全性（SI = 181.93 和 54.41）都更高。 对肝癌（HepG-2；IC = 65.08 nM）具有活性，这是 CRC 的主要转移部位，与 MMP-13 表达相关。两种衍生物在 2.67 和 1.87 nM 时诱导 DNA 损伤，与多柔比星相比，破坏 HCT-116 细胞周期并诱导 33.17%的细胞凋亡（DNA 损伤在 0.76 nM 时诱导 40.21%的细胞凋亡）。 对 MMP-10（IC = 0.205 μM）和 MMP-13（IC = 0.275 μM）的活性超过了 NNGH，并下调了与 CRC 进展相关的 HCT-116 VEGF 表达，下调率为 38%。对接和 MD 模拟了配体-受体的结合模式，并突出了 SAR。还通过计算预测了它们的 ADMET 特征、类药性和可能的非靶点。
