Total synthesis and biological evaluation of novel C2-C6 region analogues of dictyostatin.
Total synthesis and biological evaluation of novel C2-C6 region analogues of dictyostatin.
复制标题
新型C2-C6区类似物的全合成及生物学评价。
DOI：
10.1016/j.bmc.2008.10.084
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发表时间：
2009
影响因子：
3.5
通讯作者：
Wright,AmyE
中科院分区：
文献类型：
--
作者：
Paterson,Ian;Gardner,NicolaM;Guzman,Esther;Wright,AmyE
通过利用Still-Gennari HWE与常见C11-C26醛的偶联，合成了一系列微管稳定海洋天然产物dictyostatin的C2-C6修饰类似物，并在体外评价了对一系列人类癌细胞系的生长抑制作用，包括（P-糖蛋白流出介导的）紫杉醇抗性NCI/ADR细胞系。发现去除网皮抑素中的C6甲基取代基是良好耐受的，并导致抗增殖活性保留在低纳摩尔范围内（在NCI/ADR细胞系中IC 50 = 43 nM），而（2 Z，4 E）-二烯酸区域的部分和完全饱和导致生物效力的逐渐降低。发现内酯环的大小是关键的，因为C21至C19转内酯化以提供20元异网抑素类似物导致细胞毒性的显著损失。在对PANC-1细胞系进行的一系列孵育实验中，所有三种22元大环内酯类似物通过微管稳定化机制以类似于dictyostatin的方式起作用，引起细胞在G2/M期的积累和特征性致密细胞内微管束的形成。
By exploiting a Still–Gennari HWE coupling with a common C11–C26 aldehyde, a series of C2–C6 modified analogues of the microtubule-stabilising marine natural product dictyostatin were synthesised and evaluated in vitro for growth inhibition against a range of human cancer cell lines, including the (P-glycoprotein efflux-mediated) Taxol-resistant NCI/ADR cell line. Removal of the C6 methyl substituent in dictyostatin was found to be well tolerated and led to the retention of antiproliferative activity in the low nanomolar range (IC50=43nM in the NCI/ADR cell line), while partial and full saturation of the (2Z,4E)-dienoate region led to a progressive reduction in biological potency. The lactone ring size was found to be critical, as C21 to C19 translactonisation to afford 20-membered isodictyostatin analogues led to a significant loss of cytotoxicity. In a series of incubatory experiments performed on the PANC-1 cell line, all three of the 22-membered macrolide analogues acted in an analogous fashion to dictyostatin, through a mechanism of microtubule stabilization, causing both an accumulation of cells at the G2/M phase and formation of characteristic dense intracellular microtubule bundles.