Phenanthroindolizidine-based tylophora alkaloids have been reported to have potential antitumor, anti-immuno and, anti-inflammatory activity. The structure-activity relationships of a series of tylophora alkaloids were studied to guide future drug design. Our results indicate that although these compounds are structural analogs, their potency of cytotoxicity, selectivity against NF-κB signaling pathway, and their inhibitory effects against protein and nucleic acid synthesis are different. Because they do not have an identical spectrum of targets, the studied compounds are structural, but may not be functional analogs. © 2007 Elsevier Ltd. All rights reserved.