目的:从吉非替尼制备乙酰葡萄糖加合物(UTX-114,-115和-116),及其特征(例如,抗癌活性,结构性质)进行了分析。
方法:使用A431细胞检查UTX-114家族的细胞毒性和放射增敏特性。还检查了UTX-114家族化合物与表皮生长因子受体(EGFR-tyk)的酪氨酸激酶结构域之间的超分子关联。使用对接模拟技术对UTX-114家族化合物与EGFR-tyk进行交互分析。
结果:UTX-114家族显示出与吉非替尼相似的细胞毒性,IC50值为31.2μM(吉非替尼),34.3μM(UTX-114),36.8μM(UTX-115),和39.4μM(UTX-116)。UTX-114、-115和-116与吉非替尼的EGFR-tyk抑制率(IR)分别为1.515、0.983和0.551。UTX-114的EGFR-tyk抑制活性高于吉非替尼。在测试的化合物中,UTX-114还显示出最高的放射增敏活性。UTX-114表达1841个构象异构体(-8.989〜15.718kcal/mol),UTX-114的溶剂化自由能(dGW)随着构象能的增加而降低,范围在-354.955~-260.815kJ/mol之间。吉非替尼的相互作用能量,具有EGFR-tyk的UTX-114,-115和-116分别为-123.640,-144.053,-120.830和-124.658kcal/mol,分别。
结论:UTX-114在测试化合物中产生与EGFR-tyk最低的相互作用能。鉴于UTX-114和EGFR-tyk之间的关联行为,以及它的其他观察到的特性,UTX-114似乎是可行的治疗可能性。
OBJECTIVE: Acetyl glucose adducts (UTX-114, -115, and -116) were prepared from gefitinib, and their characteristics (e.g., anticancer activity, structural property) were analyzed.
METHODS: Cytotoxicity and radiosensitizing properties of the UTX-114 family were examined using A431 cells. Supramolecular associations between the UTX-114 family compounds and the tyrosine kinase domain of epidermal growth factor receptor (EGFR-tyk) were also examined. The interactive analyses of the UTX-114 family compounds with EGFR-tyk were performed using docking simulation technique.
RESULTS: The UTX-114 family showed a similar cytotoxicity as gefitinib, yielding IC50 values of 31.2 μM (gefitinib), 34.3 μM (UTX-114), 36.8 μM (UTX-115), and 39.4 μM (UTX-116). The EGFR-tyk inhibition ratios (IR) of UTX-114, -115, and -116 to gefitinib were 1.515, 0.983, and 0.551, respectively. The EGFR-tyk inhibitory activity of UTX-114 was higher than that of gefitinib. UTX-114 also showed the highest radiosensitizing activity among the tested compounds. UTX-114 expressed 1841 conformers (-8.989~15.718 kcal/mol) with the solvation free energy (dGW) of UTX-114 decreasing with increasing conformational energy, ranging between -354.955~ -260.815 kJ/mol. Interactive energies of gefitinib, UTX-114, -115, and -116 with EGFR-tyk were -123.640, -144.053, -120.830, and -124.658 kcal/mol, respectively.
CONCLUSIONS: UTX-114 yielded the lowest interaction energy with EGFR-tyk among tested compounds. Given the association behavior between UTX-114 and EGFR-tyk, along with its other observed properties, UTX-114 appears to be a viable therapeutic possibility.