Design, Synthesis, Anticancer Activity And Mechanism Study Of Curcumin-related Compounds Containing Benzyl Piperidone

Curcumin is a yellow compound isolated from the dried rhizomes of the plant Curcuma longa. Numerous studies have shown that curcumin possesses multifunctional pharmacological properties including anticancer activity, anti-oxidant activity and anti-inflammatory activity. Despite its safety, the clinical usefulness of curcumin is diminished by extensive first-pass metabolism, resulting in low oral bioavailability. In order to improve the pharmacokinetic profile, we designed and synthesized a series of curcumin-related compounds containing benzyl piperidone, we studied the activity and mechanisms, which is essential for the new drugs development.Based on the anticancer activity research work of curcumin-related compounds owned by our laboratory and auxiliaried the prediction and structural modification of computational chemistry QSAR, The main task of our research to synthesis three series of new diphenyl ketone of curcumin-related compounds. The synthesis route contain three-step reaction of alkylation, hydroxyl protection, aldehyde ketone condensation, utilizing the4-piperidine ketone hydrochloride hydrate as raw material. And then all the compounds were characterized by means of’HNMR spectrum and mass spectrum to indentified target compounds. Then all the compounds were synthesized and evaluated for their effects on cultured prostate cancer PC-3cells, pancreas cancer BxPC-3cells, colon cancer HT-29cells and lung cancer H1299cells. Inhibitory effects of these compounds on the growth of PC-3, BxPC-3, HT-29and H1299cells were determined by the MTT assay. Compounds A3、A4、 A6、A8、C3、C4、C6、C7、C8、C9and C11exhibited potent inhibitory effects on the growth of cultured PC-3, BxPC-3, HT-29and H1299cells. The IC50for A4、C4and C8were lower than0.5μM in all four cell lines, and A4、C4and C8were40-fold more active than curcumin. Based on the results of the screening anti-tumor activity and structure-activity relationship analysis, we select8compounds A5-A8and C5-C8for mechanism research, we found C8had a significant effect in prostate cancer PC-3cells by MTT assay and trypan blue assay, and the benzyl piperidone-containing compounds studied also stimulated apoptosis in PC-3cells. Mechanistic studies indicate that the effects of both curcumin and C8on PC-3 cells were associated with a decrease in phospho-Akt and phospho-Erkl/2. The present study indicates that C8may have useful effects on human cancer cells.Furthermore, several curcumin-related compounds (A10, B10, C10, E10and F10) with different linker groups were investigated for their effects in human prostate cancer CWR-22Rvl and LNCaP cell lines. The ability of these compounds to inhibit testosterone (TT)-or dihydrotestosterone (DHT)-induced AR activity was determined by an AR-linked luciferase assay and by testosterone (TT)-or dihydrotestosterone (DHT)-induced expression of prostate specific antigen (PSA). Compounds F10and E10had stronger inhibitory effects on the growth of cultured CWR-22Rvl and LNCaP cell lines, and they also had stronger stimulatory effects on apoptosis than curcumin and other curcumin-related compounds (A10, B10, C10) in CWR-22Rvl cells. E10and F10were more potent inhibitors of AR activity than curcumin, A10and B10. The strong activities of E10and F10may be correlated with a heteroatom linker. The results indicate that one of the potential mechanisms for the anticancer effect of the curcumin-related compounds was inhibition of AR pathways in human prostate cancer cells.