Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, United States.
Division of Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, United States.
Bioorg Med Chem. 2018 May 15;26(9):2354-2364. doi: 10.1016/j.bmc.2018.03.033. Epub 2018 Mar 23.
A series of arylnaphthalene lignan lactones based on the structure of the phyllanthusmins, a class of potent natural products possessing diphyllin as the aglycone, has been synthesized and screened for activity against multiple cancer cell lines. SAR exploration was performed on both the carbohydrate and lactone moieties of this structural class. These studies have revealed the importance of functionalization of the carbohydrate hydroxy groups with both acetylated and methylated analogues showing increased potency relative to those with unsubstituted sugar moieties. In addition, the requirement for the presence and position of the C-ring lactone has been demonstrated through reduction and selective re-oxidation of the lactone ring. The most potent compound in this study displayed an IC value of 18 nM in an HT-29 assay with several others ranging from 50 to 200 nM. In an effort to elucidate their potential mechanism(s) of action, the DNA topoisomerase IIa inhibitory activity of the most potent compounds was examined based on previous reports of structurally similar compounds, but does not appear to contribute significantly to their antiproliferative effects.
已合成并筛选了一系列基于 Phyllanthusmin 类强效天然产物的芳基萘木脂素内酯，该类天然产物的苷元为双二氢菲，具有抗多种癌细胞系活性。对该结构类别中的糖基和内酯部分都进行了 SAR 研究。这些研究表明，糖基上的羟基乙酰化和甲基化类似物的功能化非常重要，与未取代糖基相比，这些类似物的活性增强。此外，通过内酯环的还原和选择性再氧化，证明了 C 环内酯的存在和位置的重要性。在 HT-29 测定中，本研究中最有效的化合物的 IC 值为 18 nM，其他几种化合物的 IC 值在 50 到 200 nM 之间。为了阐明其潜在的作用机制，根据结构相似的化合物的先前报告，检查了最有效的化合物对 DNA 拓扑异构酶 IIa 的抑制活性，但似乎对其抗增殖作用没有显著贡献。
