Design and discovery of silybin analogues as antiproliferative compounds using a ring disjunctive – Based, natural product lead optimization approach

The present study reports the synthesis and anticancer activity evaluation of twelve novel silybin analogues designed using a ring disjunctive-based natural product lead (RDNPL) optimization approach. All twelve compounds were tested against a panel of cancer cells (i.e. breast, prostate, pancreatic, and ovarian) and compared with normal cells. While all of the compounds had significantly greater efficacy than silybin, derivative 15k was found to be highly potent (IC₅₀ < 1 μM) and selective against ovarian cancer cell lines, as well as other cancer cell lines, compared to normal cells. Preliminary mechanistic studies indicated that the antiproliferative efficacy of 15k was mediated by its induction of apoptosis, loss of mitochondrial membrane potential and cell cycle arrest at the sub-G1 phase. Furthermore, 15k inhibited cellular microtubules dynamic and assembly by binding to tubulin and inhibiting its expression and function. Overall, the results of the study establish 15k as a novel tubulin inhibitor with significant activity against ovarian cancer cells.