非平面fascaplysin类似物的设计、合成及抗肿瘤活性研究

Design,synthesis and antitumor activity of non-planar fascaplysin analogues

目的:基于fascaplysin的结构设计非平面fascaplysin类似物,并对其进行体外活性筛选。方法:本文基于fascaplysin结构通过断键开环思路设计了两类非平面fascaplysin类似物,采用经典的Pictet-Spengler反应,通过环合、酰化合成了四氢β-咔啉类目标化合物,采用异氰酸酯法合成了吲哚类目标化合物,并进行了细胞增殖抑制、细胞周期、凋亡实验。结果:目标化合物对肿瘤细胞增殖抑制活性最好为b5(5μmol·L^(-1)<IC_(50)<30μmol·L^(-1))。PI染色法检测细胞周期实验表明fascaplysin及b5呈现S期阻滞,a9,b3使A549细胞呈现G1期阻滞。AnnexinV/PI双染凋亡细胞检测表明化合物a9,b3及b5对A-549均产生凋亡诱导,b5诱导能力最强。结论:非平面fascaplysin类似物能够有效抑制肿瘤细胞增殖,对正常细胞的毒性较对照品有所降低,为进一步研究提供理论依据。

Objective: The non-planar fascaplysin analogues were designed based on the structure of fascaplysin and were screened in vitro. Methods: In this paper,two types of non-planar fascaplysin analogues based on the fascaplysin structure were designed by cleaving bond and opening the ring. Using the classical PictetSpengler reaction,the tetrahydro-β-carboline derivatives were synthesized by cyclization and acylation. The target compounds of indole were synthesized by isocyanate method. In order to explore the antitumor activity of 20 target compounds,cell proliferation inhibition experiments,cell cycle and apoptosis experiments were performed respectively.Results: The best inhibitory activity of target compounds on tumor cell proliferation was b5( 5 μmol·L-1< IC50<30 μmol·L-1). Cell cycle experiments indicated that fascaplysin and target compound b5 showed S phase block compared with the blank group. The target compounds a9 and b3 showed G1 arrest. Apoptosis cells were determined by AnnexinV/PI assay. The results showed that all derivatives a9,b3 and b5 had effect of inducing apoptosis on A-549,among which b5 was the strongest. Conclusion: Non-planar fascaplysin derivatives can effectively inhibit the proliferation of tumor cells,meanwhile,the toxicity to normal cells is reduced compared to the reference substance,which provide a theoretical basis for the further research.