Uesawa Yoshihiro, Sakagami Hiroshi, Ikezoe Naruhiko, Takao Koichi, Kagaya Hajime, Sugita Yoshiaki
Department of Clinical Pharmaceutics, Meiji Pharmaceutical University, Tokyo, Japan
Meikai University Research Institute of Odontology (M-RIO), Saitama, Japan.
Anticancer Res. 2017 Nov;37(11):6169-6176. doi: 10.21873/anticanres.12066.
BACKGROUND/AIM: Seventeen aurones 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 three human oral squamous cell carcinoma cell lines and three oral 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 TS by CC against tumor cells. Physicochemical, structural and quantum-chemical parameters were calculated based on the conformations optimized by force-field minimization.
Sixteen out of seventeen aurones showed relatively higher cytotoxicity and tumor specificity. Among them, (2Z)-2-[(4-hydroxyphenyl)methylene]-3(2H)-benzofuranone [] showed the highest TS value and PSE values, comparable with those of doxorubicin and higher than 5-FU, respectively. TS values were correlated with molecular shape, size and polarizability rather than the types of substituted groups.
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17种橙酮的细胞毒性和肿瘤特异性进行定量构效关系（QSAR）分析，以发现它们的新生物活性。
采用3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐（MTT）法测定对三种人口腔鳞状细胞癌细胞系和三种口腔间充质细胞的细胞毒性。通过平均50%细胞毒性浓度（CC）对正常细胞与对肿瘤细胞系的比值评估肿瘤特异性（TS）。通过将TS除以对肿瘤细胞的CC计算效价-选择性表达（PSE）值。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。
17种橙酮中的16种显示出相对较高的细胞毒性和肿瘤特异性。其中，(2Z)-2-[(4-羟基苯基)亚甲基]-3(2H)-苯并呋喃酮[ ]显示出最高的TS值和PSE值，分别与阿霉素相当且高于5-氟尿嘧啶。TS值与分子形状、大小和极化率相关，而非取代基团的类型。
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。
