Sakagami Hiroshi, Uesawa Yoshihiro, Masuda Yoshiko, Tomomura Mineko, Yokose Satoshi, Miyashiro Takaki, Murai Junichi, Takao Koichi, Kanamoto Taisei, Terakubo Shigemi, Kagaya Hajime, Nakashima Hideki, Sugita Yoshiaki
Meikai University Research Institute of Odontology (M-RIO), Meikai University, School of Dentistry, Saitama, Japan
Department of Clinical Pharmaceutics, Meiji Pharmaceutical University, Tokyo, Japan.
Anticancer Res. 2017 Nov;37(11):6161-6168. doi: 10.21873/anticanres.12065.
BACKGROUND/AIM: Eleven piperic acid esters were subjected to quantitative structure-activity relationship (QSAR) analysis based on their cytotoxicity and tumor-specificity, in order to find their new biological activities.
Cytotoxicity against four human oral squamous cell carcinoma cell lines and three oral normal mesenchymal cells was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Tumor specificity (TS) was evaluated by the ratio of the mean 50% cytotoxic concentration (CC) against normal cells to that against tumor cell lines. Potency-selectivity expression (PSE) value was calculated by dividing the TS value by CC against tumor cells. Apoptosis markers were detected by western blot analysis. Physicochemical, structural and quantum-chemical parameters were calculated based on the conformations optimized by force-field minimization.
One phenylmethyl ester and five phenylethyl esters showed relatively higher cytotoxicity and tumor specificity, that were significantly modified by introduction of hydroxyl and methoxy groups. On the other hand, phenylpropyl ester, phenylbutyl ester and decyl ester were essentially inactive. (2E,4E)-5-(3,4-methylenedioxyphenyl)-2,4-pentadienoic acid 2-(3,4-dihydroxyphenyl)ethyl ester [] had the highest TS and PSE values. This compound also stimulated the cleavage of caspase-3, suggesting the induction of apoptosis. TS values were correlated with molecular size, ionization potential, molecular shape, ionization potential and electronegativity. None of the compounds had any anti-HIV activity.
Chemical modification of the lead compound may be a potential choice for designing a new type of anticancer drugs.
背景/目的：基于11种胡椒酸酯的细胞毒性和肿瘤特异性进行定量构效关系（QSAR）分析，以发现其新的生物活性。
采用3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐（MTT）法测定对4种人口腔鳞状细胞癌细胞系和3种口腔正常间充质细胞的细胞毒性。通过正常细胞与肿瘤细胞系的平均50%细胞毒性浓度（CC）之比评估肿瘤特异性（TS）。通过将TS值除以对肿瘤细胞的CC来计算效价-选择性表达（PSE）值。通过蛋白质印迹分析检测凋亡标志物。基于通过力场最小化优化的构象计算物理化学、结构和量子化学参数。
一种苯甲酯和五种苯乙酯显示出相对较高的细胞毒性和肿瘤特异性，通过引入羟基和甲氧基可对其进行显著修饰。另一方面，苯丙酯、苯丁酯和癸酯基本无活性。(2E,4E)-5-(3,4-亚甲二氧基苯基)-2,4-戊二烯酸2-(3,4-二羟基苯基)乙酯[]具有最高的TS和PSE值。该化合物还刺激了半胱天冬酶-3的裂解，表明诱导了细胞凋亡。TS值与分子大小、电离势、分子形状、电离势和电负性相关。所有化合物均无抗HIV活性。
先导化合物的化学修饰可能是设计新型抗癌药物的潜在选择。
