Design and Synthesis of Novel 2-Substituted 11-Keto-boswellic Acid Heterocyclic Derivatives As Anti-Prostate Cancer Agents with Pin1 Inhibition Ability

A series of novel acetyl-11-keto-β-boswellic acid (AKBA) derivatives with a different electron-withdrawing group on ring A and a nitrogen heterocycle at C-24 were designed and synthesized. These semi-synthetic compounds showed improved anti-proliferative activity against prostate cancer cells over AKBA. Compound 8f bearing 2-cyano-3,11-dioxo moiety and piperazine was the most potent to inhibit growth of prostate cancer PC-3 (IC50 = 0.04 μM) and LNCaP (IC50 = 0.27 μM) cell lines. 8f caused cell cycle arrest in G2/M and induced apoptosis. 8f decreased the protein levels of anti-apoptosis protein Mcl-1, c-FLIP and cell cycle regulating protein cyclin D1. 8f inhibited the activity of Pin1, a peptidyl-prolyl cis–trans isomerase to stabilize cyclin D1. 8f represented a compound with improved anti-proliferative effects for prostate cancer therapy working through new mechanisms.