[Chemistry and Biological Activity of Diterpenoid Alkaloids].

Abstract

Diterpenoid alkaloids are major pharmaceutically active constituents of Aconitum plants. In phytochemical investigations on Aconitum japonicum subsp. subcuneatum, Aconitum yesoense var. macroyesoens, and Delphinium elatum cv. Pacific Giant (Ranunclaceae), the structures of isolated C₁₉- and C₂₀-diterpenoid alkaloids were elucidated. Three aconitine-type C₁₉-diterpenoid alkaloids, jesaconitine, aconitine, and mesaconitine, which are main components of A. japonicum subsp. subcuneatum, are significantly toxic to the central nervous system. However, lycoctonine-type C₁₉-diterpenoid alkaloids and C₂₀-diterpenoid alkaloids are less toxic. Several diterpenoid alkaloids from the genera Aconitum and Delphinium and their derivatives exhibited slight cytotoxic activity against several human tumor cell lines [A549 (lung carcinoma), DU145 (prostate carcinoma), MDA-MB-231 (triple-negative breast cancer), MCF-7 (estrogen receptor-positive, HER2-negative breast cancer), KB (identical to cervical carcinoma HeLa derived AV-3 cell line), and multidrug-resistant (MDR) subline KB-VIN]. In our course of studies on synthetic derivatives of the C₁₉-diterpenoid alkaloids delcosine and delpheline and the C₂₀-diterpenoid alkaloids lucidusculine, pseudokobusine, and kobusine, we found several derivatives showing significant cytotoxic activity and, thus, providing promising new leads for further development as antitumor agents. Notably, several diterpenoid alkaloids were more potent against MDR subline KB-VIN cells than the parental drug-sensitive KB cells. Among non-cytotoxic synthetic analogues, several lycoctonine-type C₁₉-diterpenoid alkaloid derivatives effectively and significantly sensitized MDR cells to three anticancer drugs, paclitaxel, vincristine, and doxorubicin.