Synthesis Of Cyclopamine Analogs And Evaluation Of Antiproliferative Activities On Cancer Cell In Vitro

Aberrant activation of Hedgehog (Hh) signaling pathway in adult cells has been reported to be involved in numerous malignant tumors so that the Hh signaling pathway has become the new target for antitumor drugs. Cyclopamine, a steroid alkaloid, is the firstly found inhibitors of Hh pathway targeting the switchable protein Smoothened and exhibits promising prospect in oncotherapy, but its clinical application is limited by its low acid stability, poor aqueous solubility, moderate activity and limited resourse.In this study, two series of cyclopamine analogs were designed and synthesizde from two available alkaloids, jervine and veratramine with principles of conformation restriction and analog design, with jervine and veratramine as starting materials. First, cyclopamine and nine analogs were synthesized by reduction, oxidation and methylation from jervine. Second, five analogs were synthesized by oxidation, methylation and acylation from veratramine. The structures of the yielded compounds were determined by MS, NMR. Structures of compounds4,9,10,14,15,16,17,18have not been reported previously in literatures.The target products were evaluated for their in vitro antitumor activities by tumor cells SGC-7901and Aspc-1.The effects of eighteen compounds against Aspc-1and SGC-7901cancer cells were evaluated by MTT method. The in vivo antitumor activity of the compounds will be divided into six concentrations100,80,50,30,10and1μmol· L-1respectively (cyclopamine, control). The antiproliferative activities were evaluated under investigation for48h and72h.In conclusion, compund11showed the best antitumor activites with the IC50at48h and72h as19.65and13.32μmol/L. The antitumor activities of SGC-7901better than Aspc-1. Besides, the antitumor activities of16and17were better than cyclopamine. The preliminary analysis of structure-activity relationship reveals that the methylene group at the C-11of jervine is indispensable; The groups introduced to the pyridine ring of veratramine with the appropriate size can contribute to increase inhibitory activity. The results can provide evidence for structural optimization of Hh inhibitor of cyclopamine analogs.