palau-amine and oroidin

We report herein that the oroidin-derived alkaloids palau'amine (1), dibromophakellin (2), and dibromophakellstatin (3) inhibit the proteolytic activity of the human 20S proteasome as well as the (i)20S immunoproteasome catalytic core. Palau'amine is found to prevent the degradation of ubiquitinylated proteins, including IκBα, in cell culture, which may be indicative of the potential mechanism by which these agents exhibit their exciting cytotoxic and immunosuppressive properties.

Topics: Alkaloids; Guanidines; HeLa Cells; Heterocyclic Compounds, 4 or More Rings; Humans; Imidazoles; Microscopy, Confocal; NF-kappa B; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Pyrroles; Spiro Compounds; Stereoisomerism

A Diels-Alder/rearrangement sequence is described for the construction of the core ring systems of several oroidin dimers, including ageliferin and palau'amine.

Topics: Alkaloids; Dimerization; Guanidines; Imidazoles; Marine Biology; Polymers; Pyrroles; Spiro Compounds

Two new phakellin alkaloids, (-)-7-N-methyldibromophakellin (14) and (-)-7-N-methylmonobromophakellin (15), were isolated from an Agelas sp. sponge, collected near Wewak, Papua New Guinea. Inhibition assays employing both 12- and 15-human lipoxygenase isozymes (12-HLO, 15-HLO) were used to guide the isolation of 14, and LCMS data pointed the way to uncovering 15. The structure elucidations were completed by spectroscopic data analysis and comparisons to the properties of known phakellins. The lipoxygenase IC50 data showed that 14 was modest in its selective inhibition of 12-HLO. The phakellin family is uniquely marine-derived, and comments are offered on the biogenetic insights provided by these new structures.

Topics: Alkaloids; Animals; Enzyme Inhibitors; Guanidines; Inhibitory Concentration 50; Lipoxygenase Inhibitors; Molecular Structure; Papua New Guinea; Piperazines; Porifera; Pyrroles; Spiro Compounds