Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
J Med Chem. 2010 Sep 23;53(18):6699-705. doi: 10.1021/jm100846r.
6,6,8-Triethyldesmosdumotin B (2) was discovered as a MDR-selective flavonoid with significant in vitro anticancer activity against a multidrug resistant (MDR) cell line (KB-VIN) but without activity against the parent cells (KB). Additional 2 analogues were synthesized and evaluated to determine the effect of B-ring modifications on MDR-selectivity. Analogues with a B-ring Me (3) or Et (4) group had substantially increased MDR selectivity. Three new disubstituted analogues, 35, 37, and 49, also had high collateral sensitivity (CS) indices of 273, 250, and 100, respectively. Furthermore, 2-4 also displayed MDR selectivity in an MDR hepatoma-cell system. While 2-4 showed either no or very weak inhibition of cellular P-glycoprotein (P-gp) activity, they either activated or inhibited the actions of the first generation P-gp inhibitors verapamil or cyclosporin, respectively.
6,6,8-三乙氧基德斯莫杜明 B（2）被发现是一种 MDR 选择性黄酮类化合物，对多药耐药（MDR）细胞系（KB-VIN）具有显著的体外抗癌活性，但对亲本细胞（KB）没有活性。另外合成了 2 个类似物，并对其进行了评估，以确定 B 环修饰对 MDR 选择性的影响。B 环带有 Me（3）或 Et（4）基团的类似物对 MDR 的选择性有显著提高。三个新的二取代类似物 35、37 和 49 的旁系敏感性（CS）指数分别为 273、250 和 100。此外，2-4 还在 MDR 肝癌细胞系统中表现出 MDR 选择性。虽然 2-4 对细胞 P-糖蛋白（P-gp）活性没有抑制或抑制作用很弱，但它们分别激活或抑制了第一代 P-gp 抑制剂维拉帕米或环孢菌素的作用。
