Folk medicine has long documented the purgative, anti-inflammatory, and hepatoprotective activities of the triterpenoid-class of compounds known as cucurbitacins. Anti-tumor activity has also been acknowledged by the National Cancer Institute (NCI) in tumor subpanels. However, biological activity coincides with strong cytotoxicity which makes cucurbitacins unlikely therapeutic compounds. The goal of this study is to synthesize/derivatize novel cucurbitacins to optimize activity and minimize toxicity. Several cucurbitacins were isolated and characterized from Cucurbita andreana including cucurbitacin E, E-glycoside, and B. We investigated the effect of structural modification on the hepatoprotective activity on HepG2 human-derived hepatoma cell lines for hepatoprotective activity, as well as stellate cells for anti-proliferative activity. Correlations were made between descriptors, such as lipophilicity and net charge, and hepatoprotective activity. These findings were used to direct quantitative structure-activity relationship studies (QSAR) in predicting in silico the activity of derivatized compounds and direct further transformations. Successful transformations include the reduction of cucurbitacins E, E-glycoside, and B.
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