Design and synthesis of pentacyclic triterpenoid Lantadene A analogues as antitumor agents

Lantana camara L. is one of the ten most obnoxious weeds of the world and it has encroached upon a large land area in Asia as well as other parts of the world. It has imposed a great threat to grazing animals and overall ecology.

Lantadene A (22β-angeloyloxy-3-oxoolean-12-en-28-oic acid) is a pentacyclic triterpenoid isolated from leaves of obnoxious weed Lantana camara L. Five congeners of Lantadene A (LA) were synthesized and screened for their cytotoxicity against four human cancer cell lines (HL-60, HeLa, Colon 502713 and Lung A-549) using the MTT assay. These congeners were further studied for their tumor inhibitory potential on two-stage squamous cell carcinogenesis in Swiss albino mice, induced by 7, 12-dimethylbenz [a] anthracene (DMBA) and promoted by 12-O-tetradecanoylphorbol-13-acetate (TPA). LA and its congeners showed significant cytotoxicity and antitumor activity. Typical morphological changes including cell shrinkage, chromatin condensation, and characteristic DNA ladder formation in agarose gel electrophoresis were also observed. LA induced marked concentration and time dependant inhibition of cancer cell proliferation with IC₅₀ value of 19.8±0.10µg/ml following 48h incubation. Flow cytometric analysis showed suppressed cell proliferation associated with cell cycle arrest in the G₀/G₁ phase. LA significantly inhibited cell proliferation of HL-60 cells and induced cell apoptosis through down regulating Bcl-2 and up regulating Bax expression. The peptidic caspase-3 inhibitors DEVD-CHO (NH₂-Asp-Glu-Val-Asp-CHO, 2µM), increased the viability of HL-60 cells, previously treated with LA. The results show that theses compounds have the potential to be developed as anticancer agents. This strategy will help to utilize the weed in drug development.