School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, 4072, Queensland, Australia.
Georgia Cancer Center, Molecular Oncology Program, Augusta University, Augusta, GA, 30912, USA.
Chemistry. 2019 Jan 28;25(6):1451-1455. doi: 10.1002/chem.201805420. Epub 2018 Dec 20.
D-Ring-seco-limonoids (tetranortriterpenoids), such as gedunin and xylogranin B display anti-cancer activity, acting via inhibition of Hsp90 and/or associated chaperon machinery (e.g., p23). Despite this, these natural products have received relatively little attention, both in terms of an enabling synthetic approach (which would allow access to derivatives), and as a consequence their structure-activity relationship (SAR). Disclosed herein is a generally applicable synthetic route to the BCD ring system of the seco-D-ring double bond containing limonoids. Furthermore, cell based assays revealed the first skeletal fragment that exhibited inhibition of the p23 enzyme at a level which was equipotent to that of gedunin, despite being much less structurally complex.
D-环裂环柠檬素（四环三萜类化合物），如格冬因和木菠萝素 B，通过抑制 Hsp90 和/或相关伴侣机制（如 p23）发挥抗癌活性。尽管如此，这些天然产物在合成方法（这将允许获得衍生物）以及作为结果的结构-活性关系（SAR）方面都没有得到太多关注。本文公开了一种通用的合成途径，可以获得含有 secod 环双键的裂环 D-环柠檬素的 BCD 环系统。此外，基于细胞的测定显示，第一个骨架片段表现出对 p23 酶的抑制作用，其水平与格冬因相当，尽管结构要简单得多。
