Synthesis and discovery of polyisopentenylated acylphloroglucinols with selective antiproliferative activity against breast cancer cells.

Twenty-seven polyisopentenylated acylphloroglucinols were designed and synthesized through Friedel-Crafts acylation and alkylation reactions. Among these compounds, a C-farnesylated acylphloroglucinol 13b exhibited selective antiproliferative activity against HER2+ breast cancer cells (SKBr3 and JIMT-1) and triple-negative breast cancer (TNBC) cells (MDA-MB-468), with IC₅₀ values ranging from 7.05 to 9.48 μM. Moreover, compound 13b showed low toxicity toward normal breast epithelial cells MCF-10A (CC₅₀ = 20.1 μM), indicating a favorable safety profile with selectivity indices (SI) ranging from 2.1 to 2.9. Mechanistic studies revealed that 13b inhibits breast cancer cell growth by causing G₂/M phase arrest and inducing apoptosis. These findings provide valuable insights for the development of selective antiproliferative agents against breast cancer based on polyisopentenylated acylphloroglucinol scaffold.