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Abstract
The cytotoxic marine natural product discorhabdin C contains a 2,6-dibromo-cyclohexa-2,5-diene moiety, previously proposed to be a critical feature required for biological activity. We have determined that the dienone-ring of discorhabdin C is indeed electrophilic, reacting with thiol and amine nucleophiles, affording debrominated adducts. In the case of reaction with 1-aminopentane the product contains an unusual C-2/N-18 ring closed, double-hydrate moiety. This electrophilic reactivity also extends to proteins, with lysozyme-discorhabdin C adducts being detected by ESI mass spectrometry. These results prompted further examination of an extract of discorhabdin C-producing sponge, Latrunculia (Latrunculia) trivetricillata, leading to the isolation and characterisation of a new example of a C-1/N-13 linked discorhabdin dimer that shared structural similarities with the 1-aminopentane-discorhabdin C adduct. To definitively assess the influence of the dienone moiety of discorhabdin C on cytotoxicity, a semi-synthetic hydrogenation derivative was prepared, affording a didebrominated ring-closed carbinolamine that was essentially devoid of tumour cell line cytotoxicity. Antiparasitic activity was assessed for a set of 14 discorhabdin alkaloids composed of natural products and semi-synthetic derivatives. Three compounds, (-)-discorhabdin L, a dimer of discorhabdin B and the discorhabdin C hydrogenation carbinolamine, exhibited pronounced activity towards Plasmodium falciparum K1 (IC50 30–90 nM) with acceptable to excellent selectivity (selectivity index 19–510) versus a non-malignant cell line.
Highlights
Since their first report in 1987, over 40 examples of pyrroloiminoquinone alkaloids belonging to the discorhabdin/prianosin/epinardin families have been reported
As part of our ongoing interest in the discorhabdin family of alkaloids, we examined the electrophilic reactivity of discorhabdin C towards a series of model thiol and amine nucleophiles electrophilic reactivity protein of discorhabdin towards series of model thiolby and nucleophiles and the amine-rich lysozyme, C
As part of our ongoing interest in the discorhabdin family of alkaloids, we examined the of excessreactivity triethylamine
Summary
Since their first report in 1987, over 40 examples of pyrroloiminoquinone alkaloids belonging to the discorhabdin/prianosin/epinardin families have been reported. Derived from extracts of marine sponges of the genus Latrunculia, these alkaloids have attracted much attention from both chemists and biologists due to their complex structures and associated biological activities [1,2]. While some of the first examples of the discorhabdins e.g., discorhabdin B (1) and C (2) (Figure 1) were structurally relatively simple [3,4], recent studies have unveiled unusual dimers [5], oligomers [6] and more complex polycyclic variants [7,8].
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