Tylophorine analogues are a group of phenanthroindolizidine alkaloids isolated from plants that show potent antitumor activities. DCB-3503, a novel tylophorine analogue and a lead compound, has shown potent growth inhibition (GI50 ~10-8 M) against a large number of NCI's 60 human-derived cell lines. Its mode of action is via inhibition of NF-?B and associated nuclear proteins. In this study, a CoMFA model to predict the biological activities of several DCB-3503 analogues was built as a learning set based on the pGI50 of several tylophorine analogues against a HepG2 cell line. The results show that the biological activities of DCB-3503 can be increased if R1 is modified with sterically bulky groups or electron-withdrawing groups, or R2 with electron-withdrawing groups. Compounds 8  , 21  and 22  shown in the figure were selected as the modified target compounds aiming at increasing the biological activities from DCB-3503. Synthesis of these compounds was carried out, and their structures were confirmed by NMR spectroscopy and crystallography.

Novel phenanthroindolizidine alkaloids with potent antitumor activity: A CoMFA study of derivatives of DCB-3503

246th National Meeting (2013)

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