Shimada Chiyako, Uesawa Yoshihiro, Ishii-Nozawa Reiko, Ishihara Mariko, Kagaya Hajime, Kanamoto Taisei, Terakubo Shigemi, Nakashima Hideki, Takao Koichi, Sugita Yoshiaki, Sakagami Hiroshi
Division of Pharmacology, Meikai University School of Dentistry, Sakado, Saitama, Japan.
Department of Clinical Pharmaceutics, Meiji Pharmaceutical University, Noshio, Kiyose, Tokyo, Japan.
Anticancer Res. 2014 Oct;34(10):5405-11.
Fifteen 3-styrylchromones were subjected to quantitative structure-activity relationship (QSAR) analysis based on their cytotoxicity, tumor selectivity and anti-HIV activity, in order to explore their biological activities.
Cytotoxicity against four human oral squamous cell carcinoma (OSCC) cell lines and three human oral normal cells was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Tumor-selectivity was evaluated by the ratio of the mean CC50 (50% cytotoxic concentration) against normal human oral cells to that against OSCC cell lines. Anti-HIV activity was evaluated by the ratio of CC50 to EC50 (50% cytoprotective concentration from HIV infection). Physicochemical, structural and quantum-chemical parameters were calculated based on the conformations optimized by the LowModeMD method followed by the density functional theory (DFT) method.
All 3-styrylchromone derivatives showed moderate-to-high tumor selectivity. Especially, compounds that have a methoxy group at 6-position of the chromone ring and hydroxyl group at 4'-position of phenyl group in styryl moiety [ 11: ] showed the highest tumor-selectivity. On the other hand, their cytotoxicity against normal cells showed good correlation to the descriptors that reflect hydrophobic interaction and molecular shapes.
Multivariate statistics with chemical descriptors for the location of substituted group, molecular shape and electrostatic interaction may be useful for designing the most favorable compound with higher tumor selectivity.
基于15种3-苯乙烯基色酮的细胞毒性、肿瘤选择性和抗HIV活性，对其进行定量构效关系（QSAR）分析，以探究它们的生物活性。
采用3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐（MTT）法测定对四种人口腔鳞状细胞癌（OSCC）细胞系和三种人口腔正常细胞的细胞毒性。通过正常人口腔细胞的平均CC50（50%细胞毒性浓度）与OSCC细胞系的平均CC50之比评估肿瘤选择性。通过CC50与EC50（50% HIV感染细胞保护浓度）之比评估抗HIV活性。基于通过LowModeMD方法优化构象后再采用密度泛函理论（DFT）方法计算得到的物理化学、结构和量子化学参数。
所有3-苯乙烯基色酮衍生物均表现出中到高的肿瘤选择性。特别是，色酮环6位有甲氧基且苯乙烯基部分苯基4'位有羟基的化合物[11:]表现出最高的肿瘤选择性。另一方面，它们对正常细胞的细胞毒性与反映疏水相互作用和分子形状的描述符具有良好的相关性。
利用取代基位置、分子形状和静电相互作用的化学描述符进行多变量统计，可能有助于设计出具有更高肿瘤选择性的最有利化合物。
