The bark of Annona squamosa yielded three new mono-tetrahydrofuran (THF) ring acetogenins, each bearing two flanking hydroxyls and a carbonyl group at the C-9 position. These compounds were isolated using the brine shrimp lethality assay as a guide for the bioactivity-directed fractionation. (2,4-cis and trans)-Mosinone A (1) is a mixture of ketolactone compounds bearing a threo/trans/threo ring relationship and s double bond two methylene units away from the flanking hydroxyl. The other two new acetogenins differ in their stereochemistries around the THF ring; mosin B (2) has a threo/trans/erythro configuration across the ring, and mosin C (3) possesses a threo/cis/threo relative stereochemistry. Also found was annoreticuin-9-one (4), a known acetogenin that bears a threo/trans/threo ring configuration and a C-9 carbonyl and is new to this species. The structures were elucidated based on spectroscopic and chemical methods. Compounds 1-4 all showed selective cytotoxic activity against the human pancreatic tumor cell line, PACA-2, with potency 10-100 times that of Adriamycin.