Vobasinyl–Iboga Alkaloids from Tabernaemontana elegans: Cell Cycle Arrest and Apoptosis-Inducing Activity in HCT116 Colon Cancer Cells

• Published in: Journal of natural products (Washington, D.C.) D.C.), 2016-10, Vol.79 (10), p.2624-2634
• Main Authors: Paterna, Angela, Gomes, Sofia E, Borralho, Pedro M, Mulhovo, Silva, Rodrigues, Cecília M. P, Ferreira, Maria-José U
• Format: Article
• Language: English
• Subjects: Africa; Antineoplastic Agents, Phytogenic - chemistry; Antineoplastic Agents, Phytogenic - isolation & purification; Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis - drug effects; Caspase 3 - metabolism; Cell Cycle - drug effects; Cell Cycle Checkpoints - drug effects; Colonic Neoplasms - drug therapy; Crystallography, X-Ray; Drug Screening Assays, Antitumor; HCT116 Cells; Hep G2 Cells; Humans; Ibogaine - pharmacology; Indole Alkaloids - chemistry; Indole Alkaloids - isolation & purification; Indole Alkaloids - pharmacology; L-Lactate Dehydrogenase - metabolism; Molecular Conformation; Molecular Structure; Mozambique; Nuclear Magnetic Resonance, Biomolecular; Plant Roots - chemistry; Plants, Medicinal - chemistry; Tabernaemontana - chemistry
• ISSN: 0163-3864; 1520-6025
• DOI: 10.1021/acs.jnatprod.6b00552

Phytochemical investigation of the roots of the African medicinal plant Tabernaemontana elegans led to the isolation of three new (1–3) and two known (4 and 5) bisindole alkaloids of the vobasinyl–iboga type. The structures of 1–3 were assigned by spectroscopic methods, mainly using 1D and 2D NMR experiments. All of the isolated compounds were evaluated for their cytotoxicity against HCT116 colon and HepG2 liver carcinoma cells by the MTS metabolism assay. Compounds 1–3 and 5 were found to be cytotoxic to HCT116 colon cancer cells, displaying IC50 values in the range 8.4 to >10 μM. However, the compounds did not display significant cytotoxicity against HepG2 cancer cells. The cytotoxicity of compounds 1–3 and 5 was corroborated using a lactate dehydrogenase assay. Hoechst staining and nuclear morphology assessment and caspase-3/7 activity assays were also performed for investigating the activity of compounds 1–3 and 5 as apoptosis inducers. The induced inhibition of proliferation of HCT116 cells by compounds 1 and 2 was associated with G1 phase arrest, while compounds 3 and 5 induced G2/M cell cycle arrest. These results showed that the new vobasinyl–iboga alkaloids 1–3 and compound 5 are strong inducers of apoptosis and cell cycle arrest in HCT116 colon cancer cells.