| Summary: | In a survey of the secondary metabolite chemistry profiles of ten New Zealand, one Antarctic and one South African-sourced collections of Latrunculia spp. sponges, eighteen discorhabdin alkaloids have been isolated. Four of those, namely discorhabdin K, 3-dihydro discorhabdin A, 1-thiomethyl discorhabdin G*/I, and 16a,17a-dehydro discorhabdin W were fully characterized as new natural products in the series. In addition, for the first time, five enantiomeric pairs and two sets of diastereomers of the naturallyoccurring discorhabdin alkaloids were identified. The absolute configuration of all of the chiral compounds isolated, including new natural products, has been established upon comparison of the observed experimental data with the results of time dependant density functional theory calculations of the electronic circular dichroism spectra. A structure activity relationship study on discorhabdin B, the main natural product of the Wellington-sourced sponges, has identified four reactive centres on the molecule and yielded nine novel semi-synthetic derivatives. Consequently, a new discorhabdin biosynthetic tree was proposed which highlighted discorhabdin B as a crucial precursor to a number of other naturally-occurring analogues. The importance of the iminoquinone moiety and the spirodienone ring with respect to the bioactivity of the compounds in a range of naturally-occurring discorhabdins was demonstrated. A new semi-synthetic derivative, 1-discorhabdyl discorhabdin D, was identified as a potent anti-malarial agent and has opened new possibilities for the therapeutic development of the discorhabdin alkaloids.
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