Mínguez José M, Kim Sun-Young, Giuliano Kenneth A, Balachandran Raghavan, Madiraju Charitha, Day Billy W, Curran Dennis P
Department of Chemistry, Chevron Science Center, 219 Parkman Avenue, Pittsburgh, PA 15260, USA.
Bioorg Med Chem. 2003 Jul 31;11(15):3335-57. doi: 10.1016/s0968-0896(03)00186-x.
An efficient, convergent and stereocontrolled synthesis of simplified analogues of the potent antimitotic agent (+)-discodermolide has been achieved and several small libraries have been prepared. In all the libraries, the discodermolide methyl groups at C14 and C16 and the C7 hydroxy group were removed and the lactone was replaced by simple esters. Other modifications introduced in each series of analogues were related to C11, C17 and C19 of the natural product. Key elements of the synthetic strategy included (a) elaboration of the main subunits from a common intermediate and (b) fragment couplings using Wittig reactions to install the (Z)-olefins. Library components were analyzed for microtubule-stabilizing actions in vitro, for displacement of [3H]paclitaxel from its binding site on tubulin, for antiproliferative activity against human carcinoma cells, and for cell signaling and mitotic spindle alterations by a multiparameter fluorescence cell-based screening technique. The results show that even significant structural simplification can lead to analogues with actions related to microtubule targeting.
已实现了对强效抗有丝分裂剂（+）-盘状海绵醇的简化类似物的高效、收敛性和立体控制合成，并制备了几个小型文库。在所有文库中，去除了C14和C16处的盘状海绵醇甲基以及C7羟基，并用简单酯取代了内酯。在每个类似物系列中引入的其他修饰与天然产物的C11、C17和C19有关。合成策略的关键要素包括：（a）从共同中间体精心构建主要亚基；（b）使用维蒂希反应进行片段偶联以安装（Z）-烯烃。通过基于多参数荧光细胞的筛选技术，对文库成分进行了体外微管稳定作用、[3H]紫杉醇从其在微管蛋白上结合位点的置换、对人癌细胞的抗增殖活性以及细胞信号传导和有丝分裂纺锤体改变的分析。结果表明即使进行显著的结构简化也能产生与微管靶向相关作用的类似物。
