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.

Chemotherapy refers principally to the use of small molecules to treat cancer, and natural product derivatives have been main sources of clinically using anticancer drugs. While the coumarin skeleton does not inhibit cell growth, its derivatives are often active, and numerous coumarins have been examined for antiproliferative activity against human cancer cell lines. In this study, 16 novel coumarin derivatives (1, 1a–5a, 1b, 2b, 6b, 7b, 8–13) with attached N-heterocycles, including aminopyrrolidine, aminopiperidine, aminoazepane, and indoline, were prepared and ultimately esterified or amidated with alcohols or amines, respectively. All synthesized N-heterocycles containing coumarin derivatives with alcohols, amines, and carboxylic acids were assessed for antiproliferative activity against several human cancer cell lines, containing triple-negative breast cancer (TNBC) as well as a P-glycoprotein (P-gp) overexpressing multidrug-resistant (MDR) KB subline KB-VIN. Five coumarin derivatives (3a–5a, 12, 13) showed no effect (IC50 >40 µM) against all tested cell lines. In contrast, derivative 1a showed broad-spectrum activity against four cell lines, while 1b and 10 were nearly twice as selective for KB-VIN cells as the parent KB. The coumarin derivatives 1a, 1b, and 10 were optimal for antiproliferative activity in this study and could provide a new avenue for overcoming MDR tumors. Derivatives 1a, 1b, and 10 showed MDR cell-selective antiproliferative activity, indicating that N-heterocycle-coumarins exert previously unexplored bioactivity with selective action on MDR cancer cells.