Seven lactone metabolites, namely the known plakortones B-D (1-3), the novel plakortones E (4) and F (5), and two novel γ-lactones, named simplactones A (6) and B (7), have been isolated from the Caribbean sponge Plukortis simplex, and their structures characterized by spectroscopic and chemical means. In addition, the unprecedented amino acid 8 has been isolated from the same source, and a hypothesis of its biogenetic relationship with simplactones is herein reported. Plakortones B-F and compound 8 exhibited in vitro cytotoxic activity on WEHI 164, murine fibrosarcoma cell line.