Cytotoxic Effects of Diterpenoid Alkaloids Against Human Cancer Cells

Abstract

Diterpenoid alkaloids are isolated from plants of the genera Aconitum, Delphinium, and Garrya (Ranunculaceae) and classified according to their chemical structures as C18-, C19- or C20-diterpenoid alkaloids. The extreme toxicity of certain compounds, e.g., aconitine, has prompted a thorough investigation of how structural features affect their bioactivities. Therefore, natural diterpenoid alkaloids and semi-synthetic alkaloid derivatives were evaluated for cytotoxic effects against human tumor cells [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]. Among the tested alkaloids, C19-diterpenoid (e.g., lipojesaconitine, delcosine and delpheline derivatives) and C20-diterpenoid (e.g., kobusine and pseudokobusine derivatives) alkaloids exhibited significant cytotoxic activity and, thus, provide 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.

Diterpenoid Alkaloids from the Aerial Parts of Aconitum flavum Hand.-Mazz

“…Since diterpenoid alkaloids in Aconitum were reported to commonly treat traumatic injury, arrhythmia, and rheumatism, in which ion channels or inflammation were involved in the pathophysiological process and inhibitors of ion channels or NO release were considered as potential agents for the treatment of these diseases [ 25 ], these isolated compounds were evaluated for their inhibitory effects on T-type ion channels using the whole-cell recording patch clamp method, NO production in LPS-activated RAW264.7 cells using Griess assay [ 26 ], on five human tumor cell lines [ 27 ], as well as acetylcholinesterase (AChE) [ 28 ]. As a result, compound 8 (30 μM) exhibited 64.5% inhibitory rate on Ca v 3.1 low voltage-gated Ca 2+ channel.…”

Molecular Human Targets of Bioactive Alkaloid-Type Compounds from Tabernaemontana cymose Jacq.

“…These findings suggest the possibility of use indole type alkaloids in some controlled treatments against cellular proliferation as a consequence of its potential inhibitory effect on cancer-related molecular signaling pathways. It is know how slight changes in the molecular structure of this kind of compounds could result in activity variations [ 71 , 72 ]. The strongest in silico inhibitor of cellular proliferation, 5-oxocoronaridine, could give some insight concerning to the mechanism of action indole alkaloids present in Tabernaemontana cymosa as antitumoral agents.…”

Chemistry and biological activities of hetisine-type diterpenoid alkaloids

“…88,90 Wada et al synthesized a series of acylated derivatives of the natural hetisine-type DAs kobusine (9) and pseudokobusine (105), the main constituents of A. japonicum, and evaluated their cytotoxic activities against three human cancer cell lines: lung (A549), prostate (DU145), and nasopharyngeal (KB). [91][92][93] Some of these hetisine derivatives displayed impressive cytotoxicity against all of the tested cancer cells, with IC 50 values ranging from 3.1 to 20.1 mM (Table 2). More signicantly, all of active compounds displayed potency against vincristine-resistant nasopharyngeal (KB-VIN) cell line with ratios of KB to KB-VIN greater than 0.7, in contrast with the positive control paclitaxel (KB/KB-VIN ratio, 0.0067).…”