半合成及 1-O-乙酰布瑞他尼内酯（旋覆花属植物中的一种倍半萜）新型类似物的体外细胞毒性评价

Semisynthesis and in vitro cytotoxic evaluation of new analogues of 1-O-acetylbritannilactone, a sesquiterpene from Inula britannica.

机构信息

Shaanxi Engineering Center of Bioresource Chemistry & Sustainable Utilization, College of Science, Northwest A&F University, Yangling 712100, China.

出版信息

Eur J Med Chem. 2014 Jun 10;80:71-82. doi: 10.1016/j.ejmech.2014.04.028. Epub 2014 Apr 13.

DOI:10.1016/j.ejmech.2014.04.028

PMID:24763364

Abstract

Semisynthetic analogues of the natural product 1-O-acetylbritannilactone (ABL), a sesquiterpene isolated from the medicinal plant Inula britannica, have been prepared and exhibited significant in vitro cytotoxic activities against four cell lines including three human cancer cell lines (HCT116, HEp-2 and HeLa) and one normal hamster cell line (CHO). Structure-activity relationships indicate that esterification of 6-OH (enhanced lipophilicity) and α-methylene-γ-lactone functionalities play important roles in conferring cytotoxicity. Among the tested compounds, 14 bearing a lauroyl group (12C) at the 6-OH position displayed most potent in vitro cytotoxic activity, with IC50 values between 2.91 and 6.78 μM, comparable to the positive control etoposide (VP-16, IC50 values between 2.13 and 4.79 μM). Moreover, the compound 14 triggered remarkable apoptosis at a low concentration, and induced cell cycle arrest in G2/M phase in HCT116 cells. The biological assays conducted with normal cells (CHO) revealed that all the synthetic compounds are no selective against cancer cell lines tested.

摘要

从药用植物旋覆花中分离得到的天然产物 1-O-乙酰布替内酯（ABL）的半合成类似物已被制备，并表现出对包括三种人癌细胞系（HCT116、HEp-2 和 HeLa）和一种正常仓鼠细胞系（CHO）在内的四种细胞系的显著体外细胞毒性活性。构效关系表明，6-OH（增强疏水性）和α-亚甲基-γ-内酯官能团的酯化在赋予细胞毒性方面起着重要作用。在所测试的化合物中，在 6-OH 位带有月桂酰基（12C）的 14 号化合物显示出最强的体外细胞毒性活性，IC50 值在 2.91 和 6.78 μM 之间，与阳性对照依托泊苷（VP-16，IC50 值在 2.13 和 4.79 μM 之间）相当。此外，化合物 14 在低浓度下引发显著的细胞凋亡，并诱导 HCT116 细胞中细胞周期停滞在 G2/M 期。用正常细胞（CHO）进行的生物测定表明，所有合成化合物对测试的癌细胞系均无选择性。