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| Design, synthesize dicompound of Lapatinib and Aspirin and its in vitro activity |
| YUAN Panpan1 GUO Kaili2 YAO Lin3 GUO Xiaofang4 LIU Jiping2 WANG Bin2 WANG Guoquan2 ZHU Xingmei1 |
1.Shaanxi Key Laboratory of Traditional Medicine Foundation and New Drug Research, Shaanxi University of Chinese Medicine, Shaanxi Province, Xianyang 712046, China;
2.Key Laboratory of Pharmacodynamics and Material Basis of Chinese Medicine of Shaanxi Administration of Traditional Chinese Medicine, Shaanxi Province, Xianyang 712046, China;
3.Department of Medicinal Chemistry and Pharmaceutical Analysis, School of Pharmacy, Air Force Medical University, Shaanxi Province, Xi’an 710032, China; 4.School of Science, Xi’an Technological University, Shaanxi Province, Xi’an 710021, China
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Abstract Objective To design, synthesize dicompound of Lapatinib and Aspirin, and investigate its activity in vitro. Methods Twin drug (CompdⅠ) was synthesized by using Lapatinib and Aspirin as raw materials. Human epidermal growth factor receptor 2 (HER2) positive breast cancer cells BT474 were divided into blank group, Aspirin group, Lapatinib group, and CompdⅠ group. CCK-8 method and plate cloning method were used to determine half inhibitory concentration (IC50) and cell clone formation rate; the binding of CompdⅠ to AMPK/mTOR pathway protein and cyclooxygenase 1 protein was investigated by molecular docking; the expression level of AMPK/mTOR pathway protein was revealed by Western blot. Results CompdⅠ was synthesized from Lapatinib and Aspirin by condensation reaction, and the yield was 78%, melting point was 101.7-102.7℃. The IC50 of CompdⅠ was significantly different from that of Lapatinib and Aspirin for 24, 48 h, and 72 h (P＜0.05 or P＜0.01). Compared with blank group, the clone formation rate in Aspirin group, Lapatinib group, and CompdⅠ group was lower, compared with Aspirin group and Lapatinib group, the clone formation rate in CompdⅠ group was lower, and the differences were statistically significant (P＜0.05 or P＜0.01). The binding energy absolute values of CompdⅠ with epidermal growth factor receptor (EGFR), HER2, AMPK, Akt1, and mTOR were all ≥5 kcal/mol, the binding energy of CompdⅠ with EFGR, Akt1, and mTOR was lower than that of Lapatinib, but it could not bind with cyclooxygenase 1. Compared with blank group, EGFR, HER2, p-Akt1-Ser124, p-Akt1-Ser169, Akt1, p-mTOR, and mTOR were down-regulated in CompdⅠ group and Lapatinib group, and p-Akt1-Ser169, p-mTOR were down-regulated in Aspirin group, p-AMPK and AMPK were up-regulated in CompdⅠ group, and AMPK was up-regulated in Lapatinib group, and the differences were statistically significant (P＜0.05 or P＜0.01). Compared with Lapatinib group, P-AMPK was up-regulated in CompdⅠ group, and the difference was highly statistically significant (P＜0.01). Conclusion CompdⅠ has stronger anti-HER2 proliferative activity, which acts mainly by activating AMPK, and inhibiting HER2/mTOR pathway.
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