Abstract Kigelia pinnata DC. (Bignoniaceae also referred to as K. Africana or sausage tree), is a tree which is found widely in Africa and the tropics in general. Traditionally hot aqueous extracts of fruit pods from Kigelia pinnata have been claimed to have widespread ethnomedicinal importance. A preliminary study of the components of the aqueous extracts from the fruits of Kigelia pinnata was undertaken to identify fractions with potential anti-cancer activity. A bioactivity guided fractionation process of extracts from fruits of the tree was carried out yielding a number of crude fractions, which demonstrated cytotoxicity in vitro against human melanoma cells. A number of compounds were isolated and identified within purified fractions of several fruit extracts including the dihydroisocoumarins, demethylkigelin and kigelin, a number of fatty acids, and a furonaphthoquinone, as compounds at least in part responsible for the anti-proliferative activity observed in extracted material from the fruits. We tested a number of structurally related dihydroisocoumarins for their anti-proliferative activity in order to conduct a preliminary structure-activity relationship (SAR) study. The preliminary medicinal chemistry programme clearly identified structures with enhanced anti-proliferative activity relative to the isolated compounds. In conclusion, using a bioassay fractionation approach, we have isolated and characterized several classes of compounds that exhibit biological activity against human cancer cell lines. Structurally-related derivatives of these compounds have been synthesized to develop knowledge of the structure-activity relationship for these classes of compounds. Our data to date suggest that this class of molecule has structural features that appear to be of importance in determining its activity against human cancer cells. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A175.