School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 102488, China.
Molecules. 2020 Feb 20;25(4):948. doi: 10.3390/molecules25040948.
Betulinic acid () is a star member of the pentacyclic triterpenoid family, which exhibits great prospects for antitumor drug development. In an attempt to develop novel antitumor candidates, 21 -nitrogen heterocyclic derivatives were synthetized, in addition to four intermediates, 23 of which were first reported. Moreover, they were screened for in-vitro cytotoxicity against four tumor cell lines (Hela, HepG-2, BGC-823 and SK-SY5Y) by a standard methylthiazol tetrazolium (MTT) assay. The majority of these derivatives showed much stronger cytotoxic activity than . Remarkably, the most potent compound (the half maximal inhibitory concentration (IC) of which was 2.05 ± 0.66 μM) was 12-fold more toxic in vitro than -treated Hela. Furthermore, multiple fluorescent staining techniques and flow cytometry collectively revealed that compound could induce the early apoptosis of Hela cells. Structure-activity relationships were also briefly discussed. The present study highlighted the importance of introducing nitrogen heterocyclic rings into betulinic acid in the discovery and development of novel antitumor agents.
白桦脂酸 () 是五环三萜类家族中的明星成员，在抗肿瘤药物开发方面具有广阔的前景。为了开发新型抗肿瘤候选药物，我们合成了 21-氮杂环衍生物，此外还合成了四个中间体，其中 23 个是首次报道的。此外，我们还通过标准的噻唑蓝（MTT）法筛选了这些化合物对四种肿瘤细胞系（Hela、HepG-2、BGC-823 和 SK-SY5Y）的体外细胞毒性。这些衍生物中的大多数都显示出比白桦脂酸更强的细胞毒性。值得注意的是，最有效的化合物 （其半最大抑制浓度（IC）为 2.05 ± 0.66 μM）在体外对 Hela 的毒性比 -处理的 Hela 高 12 倍。此外，多种荧光染色技术和流式细胞术共同揭示，化合物 可诱导 Hela 细胞早期凋亡。还简要讨论了构效关系。本研究强调了在发现和开发新型抗肿瘤药物时，将氮杂环引入白桦脂酸的重要性。
