Exploration of the Electrophilic Reactivity of the Cytotoxic Marine Alkaloid Discorhabdin C and Subsequent Discovery of a New Dimeric C-1/N-13-Linked Discorhabdin Natural Product

• Main Authors: Cary F. C. Lam, Melissa M. Cadelis, Brent R. Copp
• Format: Article
• Language: English
• Published: MDPI AG 2020-07-01
• Series: Marine Drugs
• Subjects: marine natural product; alkaloid; discorhabdin; electrophilic reactivity; discorhabdin dimer; antimalarial
• Online Access: https://www.mdpi.com/1660-3397/18/8/404

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, <i>Latrunculia</i> (<i>Latrunculia</i>) <i>trivetricillata</i>, 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 <i>Plasmodium falciparum</i> K1 (IC₅₀ 30–90 nM) with acceptable to excellent selectivity (selectivity index 19–510) versus a non-malignant cell line.