Madecassic acid (1) is a naturally occurring pentacyclic triterpenoid found in the traditional medicinal plant Centella asiatica (L.) Urban. This compound has been shown to possess several pharmacological activities, such as wound healing, antioxidant, and antidiabetic activities. Furthermore, a recent study gave evidence for an apoptotic effect of 1 in an in vivo model using mice bearing CT26 cancer cells. Compared to some other triterpenoid scaffolds, only a limited number of 1 derivatives are known, and few of these have been investigated with respect to their cytotoxic activity. In order to search for novel antitumor, a series of novel 1 derivatives was synthesized and screened for cytotoxicity activity against the NCI-60 panel of cancer cell lines. All the tested semisynthetic derivatives showed better antiproliferative activities than 1 itself. Among them, compound 29 showed GI50 (50% growth inhibition) values ranging from 0.3 to 0.9 μM against 26 different tumor cell lines and revealed selectivity for one colon (COLO 205) and two melanoma (SK-MEL-5 and UACC-257) cell lines at the TGI (total growth inhibition) level. The mode of action of 29 was predicted using the tool CellMiner and confirmed by a series of cell-based and biochemical assays, showing that treatment with 29 results in cell cycle arrest at the G1/S transition and disruption of the mitochondrial membrane potential in tumor cells. Considering the present results, derivative 29 represents a potential lead for the development of new anticancer agents and merits further investigation.

Novel semisynthetic derivatives of madecassic acid as potential anticancer agents

ACS Fall 2021

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