Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Hokkaido University of Science, 4-1, Maeda 7-jo 15-choume, Teine-ku, Sapporo, 006-8585, Japan.
Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599-7568, USA.
J Nat Med. 2022 Sep;76(4):796-802. doi: 10.1007/s11418-022-01629-y. Epub 2022 May 25.
The pharmacological activities of C-diterpenoid alkaloids are related to their basic skeletons (e.g., aconitine-type or lycoctonine-type). Also, few studies have been reported on the chemosensitizing effects of diterpenoid alkaloids. Consequently, this study was aimed at determining the chemosensitizing effects of synthetic derivatives of lycoctonine-type C-diterpenoid alkaloids on a P-glycoprotein (P-gp)-overexpressing multidrug-resistant (MDR) cancer cell line KB-VIN. The acyl-derivatives of delpheline and delcosine showed moderate cytotoxicity against chemosensitive cancer cell lines. Among non-cytotoxic synthetic analogs (1-14), several derivatives effectively and significantly sensitized MDR cells by interfering with the drug transport function of P-gp to three anticancer drugs, vincristine, paclitaxel, and doxorubicin. The chemosensitizing effect of derivatives 2, 4, and 6 on KB-VIN cells against vincristine were more potent than 5 μM verapamil, and derivatives 4 and 13 were more effective than 5 μM verapamil for paclitaxel. Among them, 2 in particular increased the sensitivity of KB-VIN cells to vincristine by 253-fold.
C-二萜生物碱的药理活性与其基本骨架（如乌头碱型或藜芦科碱型）有关。此外，关于二萜生物碱的化学增敏作用的研究较少。因此，本研究旨在确定藜芦科碱型 C-二萜生物碱的合成衍生物对 P-糖蛋白（P-gp）过表达多药耐药（MDR）癌细胞系 KB-VIN 的化学增敏作用。delpheline 和 delcosine 的酰基衍生物对化疗敏感的癌细胞系表现出中等细胞毒性。在非细胞毒性的合成类似物（1-14）中，有几个衍生物通过干扰 P-gp 对三种抗癌药物（长春新碱、紫杉醇和阿霉素）的药物转运功能，有效地显著增敏了 MDR 细胞。衍生物 2、4 和 6 对 KB-VIN 细胞的长春新碱的化学增敏作用强于 5 μM 维拉帕米，衍生物 4 和 13 对紫杉醇的作用强于 5 μM 维拉帕米。其中，2 特别将 KB-VIN 细胞对长春新碱的敏感性提高了 253 倍。
