PDF(Pubmed)
Abstract：
Directed structural modifications of natural products offer excellent opportunities to develop selectively acting drug candidates. Natural product hybrids represent a particular compound group. The components of hybrids constructed from different molecular entities may result in synergic action with diminished side effects. Steroidal homo- or heterodimers deserve special attention owing to their potentially high anticancer effect. Inspired by our recently described antiproliferative core-modified estrone derivatives, here, we combined them into heterodimers via Cu(I)-catalyzed azide-alkyne cycloaddition reactions. The two trans-16-azido-3-(O-benzyl)-17-hydroxy-13α-estrone derivatives were reacted with 3-O-propargyl-D-secoestrone alcohol or oxime. The antiproliferative activities of the four newly synthesized dimers were evaluated against a panel of human adherent gynecological cancer cell lines (cervical: Hela, SiHa, C33A; breast: MCF-7, T47D, MDA-MB-231, MDA-MB-361; ovarian: A2780). One heterodimer (12) exerted substantial antiproliferative activity against all investigated cell lines in the submicromolar or low micromolar range. A pronounced proapoptotic effect was observed by fluorescent double staining and flow cytometry on three cervical cell lines. Additionally, cell cycle blockade in the G2/M phase was detected, which might be a consequence of the effect of the dimer on tubulin polymerization. Computational calculations on the taxoid binding site of tubulin revealed potential binding of both steroidal building blocks, mainly with hydrophobic interactions and water bridges.
摘要：
天然产物的定向结构修饰为开发选择性作用的候选药物提供了极好的机会。天然产物杂种代表特定的化合物组。由不同分子实体构建的杂化物的组分可导致协同作用,且副作用减少。类固醇同源或异二聚体由于其潜在的高抗癌作用而值得特别关注。受我们最近描述的抗增殖核心修饰的雌酮衍生物的启发，在这里，我们通过Cu（I）催化的叠氮化物-炔环加成反应将它们组合成异二聚体。将两种反式-16-叠氮基-3-（O-苄基）-17-羟基-13α-雌酮衍生物与3-O-炔丙基-D-塞科雌酮醇或肟反应。针对一组人贴壁妇科癌细胞系（宫颈：Hela，SiHa,C33A;乳腺:MCF-7,T47D,MDA-MB-231，MDA-MB-361；卵巢：A2780）。一个异二聚体（12）对亚微摩尔或低微摩尔范围内的所有研究细胞系均具有实质性的抗增殖活性。通过荧光双重染色和流式细胞术对三种宫颈细胞系观察到明显的促凋亡作用。此外,检测到G2/M期的细胞周期阻滞，这可能是二聚体对微管蛋白聚合的影响的结果。对微管蛋白的紫杉烷结合位点的计算计算揭示了两种类固醇结构单元的潜在结合，主要与疏水相互作用和水桥。
