Hollongdione arylidene derivatives induce antiproliferative activity against melanoma and breast cancer through pro-apoptotic and antiangiogenic mechanisms

The use of natural compounds as starting point for semisynthetic derivatives has already been proven as a valuable source of active anticancer agents. Hollongdione (4,4,8,14-tetramethyl-18-norpregnan-3,20-dion), obtained by few steps from dammarane type triterpenoid dipterocarpol, was chemically modified at C2 and C21 carbon atoms by the Claisen-Schmidt aldol condensation to give a series of arylidene derivatives. The anticancer activity of the obtained compounds was assessed on NCI-60 cancer cell panel, revealing strong antiproliferative effects against a large variety of cancer cells. 2,21-Bis-[3-pyridinyl]-methylidenohollongdione 9 emerged as the most active derivative as indicated by its GI50 values in the micromolar range which, combined with its high selectivity index values, indicated its suitability for deeper biological investigation. The mechanisms involved in compound 9 antiproliferative activity, were investigated through in vitro (DAPI staining) and ex vivo (CAM assay) tests, which exhibited its apoptotic and antiangiogenic activities. In addition, compound 9 showed an overall inhibition of mitochondrial respiration. rtPCR analysis identified the more intimate activity at pro-survival/proapoptotic gene level. Collectively, the hollongdione derivative stand as a promising therapeutic option against melanoma and breast cancer provided that future in vivo analysis will certify its clinical efficacy.

Automated summary

The use of natural compounds as starting points for semisynthetic derivatives has shown to be a valuable source of active anticancer agents. Hollongdione, obtained from dammarane type triterpenoid dipterocarpol, was modified and a series of derivatives were obtained. These derivatives displayed strong anticancer activity, with 2,21-Bis-[3-pyridinyl]-methylidenohollongdione 9 being the most active one. It showed apoptotic and antiangiogenic activities, and also inhibited mitochondrial respiration. Further analysis at the gene level confirmed its pro-survival/proapoptotic activity. Hollongdione derivatives have potential as therapeutic options for melanoma and breast cancer.