Abstract：
The close association between inflammation and cancer inspired the synthesis of a series of 1,3,4-oxadiazole derivatives (compounds H4-A-F) of 6-methoxynaphtalene. The chemical structures of the new compounds were validated utilizing Fourier-transform infrared, proton nuclear magnetic resonance, and carbon-13 nuclear magnetic resonance spectroscopic techniques and CHN analysis. Computer-aided drug design methods were used to predict the compounds biological target, ADMET properties, toxicity, and to evaluate the molecular similarities between the design compounds and erlotinib, a standard epidermal growth factor receptor (EGFR) inhibitor. The antiproliferative effects of the new compounds were evaluated by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay, cell cycle analysis, apoptosis detection by microscopy, quantitative reverse transcription-polymerase chain reaction, and immunoblotting, and EGFR enzyme inhibition assay. In silico analysis of the new oxadiazole derivatives indicated that these compounds target EGFR, and that compounds H4-A, H4-B, H4-C, and H4-E show similar molecular properties to erlotinib. Additionally, the results indicated that none of the synthesized compounds are carcinogenic, and that compounds H4-A, H4-C, and H4-F are nontoxic. Compound H4-A showed the best-fit score against EGFR pharmacophore model, however, the in vitro studies indicated that compound H4-C was the most cytotoxic. Compound H4-C caused cytotoxicity in HCT-116 colorectal cancer cells by inducing both apoptosis and necrosis. Furthermore, compounds H4-D, H4-C, and H4-B had potent inhibitory effect on EGFR tyrosine kinase that was comparable to erlotinib. The findings of this inquiry offer a basis for further investigation into the differences between the synthesized compounds and erlotinib. However, additional testing will be needed to assess all of these differences and to identify the most promising compound for further research.
摘要：
炎症与癌症之间的紧密联系激发了一系列6-甲氧基萘的1,3,4-恶二唑衍生物（化合物H4-A-F）的合成。新化合物的化学结构进行了验证，利用傅里叶变换红外，质子核磁共振,碳-13核磁共振波谱技术和CHN分析。计算机辅助药物设计方法用于预测化合物的生物靶标,ADMET属性，毒性,并评估设计化合物和厄洛替尼之间的分子相似性，标准表皮生长因子受体（EGFR）抑制剂。通过3-（4,5-二甲基-2-噻唑基）-2,5-二苯基-2H-四唑溴化物测定法评估了新化合物的抗增殖作用，细胞周期分析,通过显微镜检测凋亡，定量逆转录聚合酶链反应，和免疫印迹,和EGFR酶抑制测定。新的恶二唑衍生物的计算机模拟分析表明，这些化合物靶向EGFR，化合物H4-A，H4-B,H4-C,和H4-E显示与厄洛替尼相似的分子特性。此外,结果表明，合成的化合物都不是致癌的，化合物H4-A，H4-C,和H4-F是无毒的。化合物H4-A显示最适合EGFR药效团模型的评分，然而,体外研究表明化合物H4-C的细胞毒性最强。化合物H4-C通过诱导细胞凋亡和坏死在HCT-116结直肠癌细胞中引起细胞毒性。此外，化合物H4-D,H4-C,H4-B对EGFR酪氨酸激酶的抑制作用与厄洛替尼相当.该调查的结果为进一步研究合成的化合物与厄洛替尼之间的差异提供了基础。然而,还需要进行额外的检测,以评估所有这些差异,并确定最有希望进一步研究的化合物.
