Semisynthesis of Novel Dispiro-pyrrolizidino/thiopyrrolizidino-oxindolo/indanedione Natural Product Hybrids of Parthenin Followed by Their Cytotoxicity Evaluation

Natural products possess unique and broader intricacies
in the
chemical space and have been essential for drug discovery. The crucial
factor for drug discovery success is not the size of the library but
rather its structural diversity. Although reports on the number of
new structurally diverse natural products (NPs) have declined recently,
researchers follow the next logical step: synthesizing natural product
hybrids and their analogues using the most potent tool, diversity-oriented
synthesis (DOS). Here, we use weed Parthenium hysterophorus as a source of parthenin for synthesis of novel dispiro-pyrrolizidino/thiopyrrolizidino-oxindolo/indanedione
natural product hybrids of parthenin via chemo-, regio-, and stereoselective
azomethine ylide cycloaddition. All synthesized compounds were characterized
through a detailed analysis of one-dimensional (1D) and two-dimensional
(2D) NMR and HRMS data, and the stereochemistries of the compounds
were confirmed by X-ray diffraction analysis. All compounds were evaluated
for their cytotoxicity against four cell lines (HCT-116, A549, Mia-Paca-2,
and MCF-7), and compound 6 inhibited the HCT-116 cells
with an IC50 of 5.0 ± 0.08 μM.

天然产物在化学空间中拥有独特且更为宽泛的结构复杂度，且在药物发现领域始终发挥着不可或缺的核心作用。药物研发取得成功的关键要素并非化合物库的体量，而是其结构多样性。尽管近期关于新型结构多样性天然产物（Natural Products）的报道数量有所下滑，但研究者们已顺理成章地转向下一步研究：借助最具效力的合成工具——定向多样性合成（Diversity-Oriented Synthesis，缩写为DOS）——来制备天然产物杂合体及其类似物。本研究以杂草银胶菊（Parthenium hysterophorus）为银胶菊素（parthenin）的来源，通过化学选择性、区域选择性及立体选择性的甲亚胺叶立德环加成反应，合成了一系列银胶菊素的新型双螺环吡咯烷并/硫代吡咯烷并-羟吲哚/茚二酮类天然产物杂合体。所有合成产物均通过一维（1D）及二维（2D）核磁共振波谱（NMR）与高分辨质谱（HRMS）的详细分析完成结构表征，并借助X射线衍射分析确认了化合物的立体化学构型。研究团队对所有化合物开展了针对4种细胞系（HCT-116、A549、Mia-Paca-2及MCF-7）的细胞毒性评价，其中化合物6对HCT-116细胞的半数抑制浓度（IC50）为5.0 ± 0.08 μM。