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By use of bioassay (murine P388 lymphocytic leukemia cell line) guided isolation procedures, extracts of the Republic of Singapore marine sponge Hymeniacidon sp. were found to contain demethyloxyaaptamine (1) and aaptamine (3) as prominent cancer cell growth inhibitory constituents accompanied by the trace, albeit more active, component isoaaptamine (4). The isolation, X-ray structure elucidation, and antineoplastic and antimicrobial activities of isoaaptamine (4) have been summarized. Because of instability, isoaaptamine (4) was converted to a stable sodium phosphate prodrug designated hystatin 1 (7).

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Aaptamine (1) was used as starting material for synthetic transformation to isoaaptamine (2), 9-demethylaaptamine (5), and 4-methylaaptamine (6). A general method for the selective O-demethylation of such 1H-benzo[de][1,6]-naphthyridine (1) marine sponge constituents at position C-9 has been developed. Selective O-demethylation of aaptamine (1) and 1-methylaaptamine (11) with 48% hydrobromic acid led to 9-demethylaaptamine (5) and isoaaptamine (2), respectively. A selection of other aaptamine derivatives were synthesized, and their structures were unambiguously determined by X-ray methods. In addition, their cancer cell growth inhibitory properties were evaluated against the murine P388 lymphocytic cell line and a minipanel of human cancer cell lines. Evaluation as inhibitors of the PKC signal transduction pathway and against a selection of microorganisms was also undertaken. Aaptamine derivatives 3 and 5 had broad-spectrum antimicrobial activities.