Chan Kin-Fai, Zhao Yunzhe, Chow Toby W S, Yan Clare S W, Ma Dik Lung, Burkett Brendan A, Wong Iris L K, Chow Larry M C, Chan Tak Hang
Department of Applied Biology and Chemical Technology and Laboratory of the Institute of Molecular Technology for Drug Discovery and Synthesis, The Hong Kong Polytechnic University, Hong Kong SAR.
ChemMedChem. 2009 Apr;4(4):594-614. doi: 10.1002/cmdc.200800413.
We recently described the modulatory activities of apigenin homodimers linked by ethylene glycol units in multidrug- resistant breast cancer and leukemic cells overexpressing ABCB1 (P-glycoprotein, P-gp). To further improve the potency of these dimers, a small library of flavonoid homodimers and heterodimers were synthesized, and their in vitro activity in reversing cellular resistance to paclitaxel, along with structure-activity relationships (SAR), were evaluated using a P-gp-expressing human breast cancer cell line. Among these synthesized homodimers, many showed more potent reversing activity than that of the parent compound and verapamil. Two compounds in particular showed promising reversing activity at sub-micromolar concentrations with no cytotoxic effects. Regarding SAR trends, flavonoid dimers with nonpolar and hydrophobic substituents (e.g., methyl and ethyl groups) generally showed more potent resistance-reversing activity than that of dimers with polar and hydrophilic substituents (e.g. hydroxy groups) at the C3, C6, and C7 positions, but not at C5. In terms of substituent steric bulk at C6, it was found that the flavonoid dimer with methyl groups was optimal, with bulkier substituents leading to lower reversing activity. Comparisons of flavonoid heterodimers with the corresponding homodimers revealed that the two binding sites on P-gp for flavonoid moieties are quite similar to each other. Besides paclitaxel, these new compounds also increased drug accumulation and enhanced the cytotoxicity of other cancer drugs such as doxorubicin, vincristine, and vinblastine by decreasing the IC(50) values 4-45-fold.
我们最近描述了由乙二醇单元连接的芹菜素同二聚体在多药耐药乳腺癌和过表达ABCB1（P-糖蛋白，P-gp）的白血病细胞中的调节活性。为了进一步提高这些二聚体的效力，合成了一个黄酮类同二聚体和异二聚体的小型文库，并使用表达P-gp的人乳腺癌细胞系评估了它们在逆转细胞对紫杉醇耐药性方面的体外活性以及构效关系（SAR）。在这些合成的同二聚体中，许多显示出比母体化合物和维拉帕米更强的逆转活性。特别是两种化合物在亚微摩尔浓度下显示出有前景的逆转活性且无细胞毒性作用。关于SAR趋势，在C3、C6和C7位带有非极性和疏水取代基（如甲基和乙基）的黄酮类二聚体通常比带有极性和亲水取代基（如羟基）的二聚体显示出更强的耐药逆转活性，但在C5位并非如此。就C6位取代基的空间体积而言，发现带有甲基的黄酮类二聚体是最佳的，取代基体积更大则导致逆转活性更低。黄酮类异二聚体与相应同二聚体的比较表明，P-gp上黄酮类部分的两个结合位点彼此非常相似。除了紫杉醇，这些新化合物还通过将IC(50)值降低4至45倍增加了药物积累并增强了其他癌症药物如阿霉素、长春新碱和长春花碱的细胞毒性。
