The Search for Antiproliferative Withanolides from Solanaceous Species of the US

As part of a decade-long International Cooperative Biodiversity Groups (ICBG) program to explore the chemical diversity of plants from Latin America, several genera in the Solanaceae afforded a variety of withanolides with important biological activities. The identification of anti-proliferative withanolides from Vassobia breviflora, coupled with challenges in obtaining additional biomass from the source countries, prompted us to search for alternative sources in plants of the United States Midwest region.

Bioassay-guided fractionation and chemical investigation of Physalis longifolia Nutt. from Kansas, identified over 30 withanolides, 14 of which are new natural products. These compounds were evaluated for cytotoxic activities against a multiple series of cancer cell lines leading to the discovery of 15 withanolides, with IC₅₀ values in the range of 0.067 – 9.3µM with selectivity of 3 to 20 fold compared to normal fetal fibroblasts. A mechanism of action study showed that withanolides induce apoptosis, shift the cell cycle to GM2, and inhibit key signaling pathways. Medicinal chemistry identified natural and semi-synthetic analogs with unique properties through structure-activity relationship analysis.

Withaferin A and its new 19-OH derivative (withalongolide A) were further evaluated in preclinical studies in various metastatic murine models including medullary thyroid cancer, head and neck squamous cell carcinomas and uveal melanoma. These withanolides were shown to significantly reduce tumor growth in vivo by inhibiting multiple targets important for tumor survival, which justifies further evaluation of these and related compounds for the treatment of metastatic cancers.