Bioactivity-directed fractionation of the leaves of Annona muricata resulted in the isolation of annopentocins A (1), B (2), and C(3), and cis- and trans-annomuricin-D-ones (4, 5). Compounds 1-3 are the first acetogenins reported bearing a mono-tetrahydrofuran (THF) ring with one flanking hydroxyl, on the hydrocarbon side, and another hydroxyl, on the lactone side, that is one carbon away from the THF ring. Compounds 4 and 5 were obtained in a mixture and are new mono-THF ring acetogenins bearing two flanking hydroxyls and an erythro-diol located between the THF and the ketolactone rings. Compound 1 was selectively cytotoxic to pancreatic carcinoma cells (PACA-2), and 2 and 3 were selectively cytotoxic to lung carcinoma cells (A-549); the mixture of 4 and 5 was selectively cytotoxic for the lung (A-549), colon (HT-29), and pancreatic (PACA-2) cell lines with potencies equal to or exceeding those of Adriamycin.