新型环状单羰姜黄素类似物的合成及其抗乳腺癌活性研究  

Synthesis and anti-breast cancer activity of novel cyclic mono-carbonyl curcumin analogues

作　　者：冯先虎 陈泳洁 陈林 侯益 曹婉君 苏强 FENG Xianhu;CHEN Yongjie;CHEN Lin;HOU Yi;CAO Wanjun;SU Qiang(Dept.of Pharmacy,Beijing Anzhen Nanchong Hospital,Capital Medical University&Nanchong Central Hospital,Sichuan Nanchong 637500,China;Dept.of Clinical Pharmacy,Zhongjiang County People’s Hospital,Sichuan Deyang 618100,China)

机构地区：[1]首都医科大学附属北京安贞医院南充医院·南充市中心医院药学部,四川南充637500 [2]中江县人民医院临床药学科,四川德阳618100

出　　处：《中国药房》2025年第5期563-567,共5页China Pharmacy

基　　金：四川省自然科学基金项目(No.2022NSFSC0711);南充市科技项目(市校科技战略合作专项)(No.22SXQT0166)。

摘　　要：目的设计并合成单羰基姜黄素类似物,并考察其抗乳腺癌活性。方法通过羟醛缩合反应获得单羰基姜黄素类似物F1、F2和F3,采用MTT法检测其抗肿瘤(包括人乳腺癌细胞MCF-7和人肺癌细胞A549)活性[以半数抑制浓度(IC_(50))评估],并与姜黄素进行比较。根据生物信息学分析方法分别获取F1、F2和F3作用于乳腺癌的第一核心蛋白,并进行分子对接验证。采用细胞实验进一步考察高、中、低浓度(16、8、4μmol/L)的F1、F2和F3对MCF-7细胞中对应第一核心蛋白以及中浓度的F1、F2和F3对细胞中剪切型胱天蛋白酶3(cleaved-caspase-3)表达的影响。结果与姜黄素相比,F1、F2和F3对A549、MCF-7细胞的IC5(0 F2对A549细胞的IC_(50)除外)均显著降低(P<0.05或P<0.01),其中F2对MCF-7细胞的IC_(50)最小,为(9.67±1.27)μmol/L。生物信息学分析结果显示,F1、F2和F3与其对应第一核心蛋白表皮生长因子受体(EGFR)、蛋白激酶B(AKT)、AKT的亲和力指数分别为5.9092、8.4025和6.4866。高浓度的F1可显著降低MCF-7细胞中EGFR蛋白磷酸化水平(P<0.01),低、中、高浓度的F2和高浓度的F3均可显著降低MCF-7细胞中AKT蛋白磷酸化水平(P<0.05或P<0.01),中浓度的F1、F2、F3均可显著升高MCF-7细胞中cleaved-caspase-3蛋白表达水平(P<0.01)。结论设计合成的单羰基姜黄素类似物F1、F2、F3均具有良好的抗乳腺癌活性,其中F2的抗乳腺癌活性更好。OBJECTIVE To design and synthesize mono-carbonyl curcumin analogues(MCACs)and investigate the activities of them against breast cancer.METHODS The analogues F1,F2,and F3 were obtained by aldol condensation reaction,and their antitumor activities(including the activities of human breast cancer cell MCF-7 and human lung cancer cell A549)were detected by MTT assay[evaluated with half inhibitory concentration(IC_(50))].The results of MTT assay were compared with those of curcumin.Bioinformatics methods were used to collect the core targets of analogues F1,F2 and F3 acting on breast cancer,and then molecular docking verification was carried out.The cell experiments were conducted to investigate the effects of high,medium and low concentrations(16,8,4μmol/L)of F1,F2 and F3 on the expression of the first core target protein as well as the effects of medium concentration of F1,F2 and F3 on the expression of cleaved-caspase-3.RESULTS Compared with curcumin,IC_(50) of analogues F1,F2 and F3 to A549 and MCF-7 cells(except for IC_(50) of analogue F2 to A549 cells)were decreased significantly(P<0.05 or P<0.01);among them,IC_(50) of analogue F2 to MCF-7 cell was the lowest,being(9.67±1.27)μmol/L.Bioinformatics analysis showed that index of affinity of analogues F1,F2 and F3 with the first core target epidermal growth factor receptor(EGFR),protein kinase B(AKT)and AKT were 5.9092,8.4025 and 6.4866,respectively;high concentration of F1 could significantly reduce the phosphorylation level of EGFR protein in MCF-7 cells(P<0.01),while low,medium,and high concentrations of F2 and high concentration of F3 could significantly reduce the phosphorylation level of AKT protein in MCF-7 cells(P<0.05 or P<0.01).Medium concentration of F1,F2,and F3 could significantly increase the expression level of cleavedcaspase-3 protein in MCF-7 cells(P<0.01).CONCLUSIONS Designed and synthesized MCACs F1,F2 and F3 all have good antibreast cancer activity,and F2 has better anti-breast cancer activity.

关 键 词：姜黄素 单羰基姜黄素类似物 乳腺癌 羟醛缩合反应 生物信息学 分子对接 细胞凋亡 

分 类 号：R914[医药卫生—药物化学] R965[医药卫生—药学]