手性曼诺内酯异构体的构效依赖性抗白血病作用：重新点燃对这些海绵衍生的甾体的研究兴趣。

The Configuration-Dependent Anti-Leukemic Effect of Manoalide Stereoisomers: Reignite Research Interest in these Sponge-Derived Sesterterpenoids.

机构信息

PhD Program in Clinical Drug Development of Herbal Medicine, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan; Graduate Institute of Pharmacognosy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan; Traditional Herbal Medicine Research Center, Taipei Medical University Hospital, Taipei 11031, Taiwan.

Graduate Institute of Marine Biotechnology, National Dong Hwa University, Pingtung 94450, Taiwan; National Museum of Marine Biology & Aquarium, Pingtung 94450, Taiwan.

出版信息

Bioorg Chem. 2021 Sep;114:105150. doi: 10.1016/j.bioorg.2021.105150. Epub 2021 Jul 7.

DOI:10.1016/j.bioorg.2021.105150

PMID:34328853

Abstract

Manoalide was studied as a potential anti-inflammatory agent for the last forty years and more than 200 publications and 180 patents were reported on this compound. However, the configurations at positions 24 and 25 and configuration-dependent bioactivity were not yet studied. In the current report, ten manoalide-like sesterterpenoids were isolated from Luffariella sp. (1-10). These stereoisomers were identified and separated for the first time since 1980 and their configurations at positions 24 and 25 were determined by analyzing their spectroscopic spectra. The configuration-dependent anti-proliferative activity of manoalide derivatives was examined by evaluating their effect on four leukemic cancer cell lines (Molt 4, K562, Sup-T1, and U937). The 24R,25S-isomers exhibited the most potent activity (IC 0.50-7.67 μM). The anti-proliferative mechanism of action of 24R,25S-manoalide (7) was further studied on Molt 4 cells. Compound 7 exhibited apoptotic activity on Molt 4 cells through the disruption of mitochondrial membrane potential (MMP) and the generation of intracellular reactive oxygen species (ROS). It also inhibited the activity of human topoisomerase I and II. The apoptotic-inducing effect of 7 was further supported by the in vivo experiment by suppressing the volume of xenograft tumor growth (66.11%) compared with the control.

摘要

曼诺内酯作为一种潜在的抗炎药物，在过去的四十年中得到了广泛的研究，相关文献超过 200 篇，专利超过 180 项。然而，其 24 位和 25 位的构型以及构效关系的生物活性尚未得到研究。在本报告中，从 Luffariella sp.（1-10）中分离得到了十个曼诺内酯类似物的甾体化合物。这些立体异构体自 1980 年以来首次被鉴定和分离，并通过分析其光谱确定了它们在 24 位和 25 位的构型。通过评估它们对四种白血病癌细胞系（Molt 4、K562、Sup-T1 和 U937）的影响，研究了曼诺内酯衍生物的构效关系依赖性抗增殖活性。24R,25S-异构体表现出最强的活性（IC 0.50-7.67 μM）。进一步在 Molt 4 细胞上研究了 24R,25S-曼诺内酯（7）的抗增殖作用机制。化合物 7 通过破坏线粒体膜电位（MMP）和产生细胞内活性氧物种（ROS），对 Molt 4 细胞表现出凋亡活性。它还抑制了人拓扑异构酶 I 和 II 的活性。通过抑制异种移植肿瘤生长的体积（与对照组相比为 66.11%），在体内实验中进一步证实了 7 的诱导凋亡作用。