isoaaptamine and Leukemia-P388

As part of an investigation to generate optimized drug leads from marine natural pharmacophores for the treatment of neoplastic and infectious diseases, a series of novel isoaaptamine analogs were prepared by coupling acyl halides to the C9 position of isoaaptamine (2) isolated from the Aaptos sponge. This library of new semisynthetic products was evaluated for biological activity against HIV-1, Mtb, AIDS-OI, tropical parasitic diseases, and cancer. Compound 4 showed potent activity against HIV-1 (EC(50) 0.47microg/mL), compound 19 proved to possess remarkable activity against Mycobacterium intracellulare with an IC(50) and MIC value of 0.15 and 0.31microg/mL, while compounds 4 and 17 possessed anti-leishmanial activity with IC(50) values of 0.1 and 0.4microg/mL, respectively. Compounds 16 and 17 showed antimalarial activity with EC(50) values of 230 and 240ng/mL, respectively, and compound 14 exhibited an EC(50) of 0.05microM against the Leukemia cell line K-562.

Topics: AIDS-Related Opportunistic Infections; Animals; Anti-Bacterial Agents; Anti-HIV Agents; Antimalarials; Antineoplastic Agents; Bacteria; HIV-1; Humans; Leishmania donovani; Leukemia P388; Malaria; Mice; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Naphthyridines; Porifera; Tumor Cells, Cultured

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).

Topics: Animals; Antineoplastic Agents; Crystallography, X-Ray; Drug Screening Assays, Antitumor; Leukemia P388; Molecular Structure; Naphthyridines; Oceans and Seas; Phosphates; Porifera; Prodrugs; Tumor Cells, Cultured

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.

Topics: Animals; Antineoplastic Agents; Bacteria; Candida albicans; Cryptococcus neoformans; Drug Screening Assays, Antitumor; Leukemia P388; Mice; Microbial Sensitivity Tests; Molecular Structure; Naphthyridines; Porifera; Structure-Activity Relationship; Tumor Cells, Cultured