Ye Jiahui, Mao Longfei, Xie Luoyijun, Zhang Rongjun, Liu Yulin, Peng Lizeng, Yang Jianxue, Li Qingjiao, Yuan Miaomiao
The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China.
School of Chemistry and Chemical Engineering, Henan Engineering Research Center of Chiral Hydroxyl Pharmaceutical, Henan Normal University, Xinxiang, China.
Front Pharmacol. 2021 Oct 26;12:753676. doi: 10.3389/fphar.2021.753676. eCollection 2021.
Chemotherapy is the most common clinical treatment for non-small cell lung cancer (NSCLC), but low efficiency and high toxicity of current chemotherapy drugs limit their clinical application. Therefore, it is urgent to develop hypotoxic and efficient chemotherapy drugs. Theophylline, a natural compound, is safe and easy to get, and it can be used as a modified scaffold structure and hold huge potential for developing safe and efficient antitumor drugs. Herein, we linked theophylline with different azide compounds to synthesize a new type of 1,2,3-triazole ring-containing theophylline derivatives. We found that some theophylline1,2,3-triazole compounds showed a good tumor-suppressive efficacy. Especially, derivative d17 showed strong antiproliferative activity against a variety of cancer cells including H460, A549, A2780, LOVO, MB-231, MCF-7, OVCAR3, SW480, and PC-9. It is worth noting that the two NSCLC cell lines H460 H and A549 are sensitive to compound d17 particularly, with IC50 of 5.929 ± 0.97 μM and 6.76 ± 0.25 μM, respectively. Compound d17 can significantly induce cell apoptosis by increasing the ratio of apoptotic protein Bax/Bcl-2 by downregulating the expression of phosphorylated Akt protein, and it has little toxicity to normal hepatocyte cells LO2 at therapeutic concentrations. These data indicate that these theophylline acetic acid-1,2,3-triazole derivatives may be potential drug candidates for anti-NSCLC and are worthy of further study.
化疗是治疗非小细胞肺癌（NSCLC）最常见的临床治疗方法，但目前化疗药物的低效率和高毒性限制了它们的临床应用。因此，开发低毒高效的化疗药物迫在眉睫。茶碱是一种天然化合物，安全易得，可作为修饰的支架结构，在开发安全高效的抗肿瘤药物方面具有巨大潜力。在此，我们将茶碱与不同的叠氮化合物连接，合成了一种新型含1,2,3-三唑环的茶碱衍生物。我们发现一些茶碱-1,2,3-三唑化合物显示出良好的肿瘤抑制效果。特别是，衍生物d17对多种癌细胞，包括H460、A549、A2780、LOVO、MB-231、MCF-7、OVCAR3、SW480和PC-9，表现出较强的抗增殖活性。值得注意的是，两种NSCLC细胞系H460和A549对化合物d17尤为敏感，IC50分别为5.929±0.97 μM和6.76±0.25 μM。化合物d17可通过下调磷酸化Akt蛋白的表达，增加凋亡蛋白Bax/Bcl-2的比例，显著诱导细胞凋亡，且在治疗浓度下对正常肝细胞LO2毒性很小。这些数据表明，这些茶碱乙酸-1,2,3-三唑衍生物可能是抗NSCLC的潜在候选药物，值得进一步研究。
