School of Chinese Medicine, China Medical University, Taichung, Taiwan.
PLoS One. 2012;7(5):e37897. doi: 10.1371/journal.pone.0037897. Epub 2012 May 29.
In a structure-activity relationship (SAR) study, 3-methoxy-1,4-phenanthrenequinones, calanquinone A (6a), denbinobin (6b), 5-OAc-calanquinone A (7a) and 5-OAc-denbinobin (7b), have significantly promising cytotoxicity against various human cancer cell lines (IC(50) 0.08-1.66 µg/mL). Moreover, we also established a superior pharmacophore model for cytotoxicity (r = 0.931) containing three hydrogen bond acceptors (HBA1, HBA2 and HBA3) and one hydrophobic feature (HYD) against MCF-7 breast cancer cell line. The pharmacophore model indicates that HBA3 is an essential feature for the oxygen atom of 5-OH in 6a-b and for the carbonyl group of 5-OCOCH(3) in 7a-b, important for their cytotoxic properties. The SAR for moderately active 5a-b (5-OCH(3)), and highly active 6a-b and 7a-b, are also elaborated in a spatial aspect model. Further rational design and synthesis of new cytotoxic phenanthrene analogs can be implemented via this model. Additionally, employing a ChemGPS-NP based model for cytotoxicity mode of action (MOA) provides support for a preliminary classification of compounds 6a-b as topoisomerase II inhibitors.
在构效关系（SAR）研究中，3-甲氧基-1,4-菲醌、卡拉醌 A（6a）、去甲二氢血根碱（6b）、5-OAc-卡拉醌 A（7a）和 5-OAc-去甲二氢血根碱（7b）对多种人类癌细胞系具有显著的细胞毒性（IC50 为 0.08-1.66μg/mL）。此外，我们还建立了一个针对 MCF-7 乳腺癌细胞系的具有优越的细胞毒性药效团模型（r = 0.931），该模型包含三个氢键受体（HBA1、HBA2 和 HBA3）和一个疏水特征（HYD）。药效团模型表明，HBA3 是 6a-b 中 5-OH 的氧原子和 7a-b 中 5-OCOCH(3)的羰基的必需特征，对于它们的细胞毒性性质非常重要。对中等活性的 5a-b（5-OCH(3)）和高活性的 6a-b 和 7a-b 的 SAR 也在空间方面模型中进行了阐述。通过该模型可以进一步对新型细胞毒性菲醌类似物进行合理设计和合成。此外，采用基于 ChemGPS-NP 的细胞毒性作用模式（MOA）模型为化合物 6a-b 作为拓扑异构酶 II 抑制剂提供了初步分类的支持。
