A Quarter Century of Marine Biodiscovery in Algoa Bay, South Africa.

Algoa Bay, the largest crenulate bay on the southeastern coast of South Africa, is currently one of the most well-studied marine ecosystems in southern Africa. A plethora of endemic marine invertebrates inhabits the benthic reefs on the western edge of the Bay in close proximity to South Africa's sixth largest city. Over the past 25 years, South African marine natural products chemists, together with international collaborators from the US National Cancer Institute and other US institutions, have focused their attention on Algoa Bay's benthic marine invertebrates as a potential source of new anticancer compounds. This review commemorates a quarter of a century of marine biodiscovery in Algoa Bay and presents the structures and bioactivities of 49 new and 36 known specialized metabolites isolated from two molluscs, eight ascidians, and six sponges. Thirty-nine of these compounds were cytotoxic to cancer cells in vitro with 20 exhibiting moderate to potent cytotoxicity. Six other compounds exhibited antimicrobial activity. Foremost among the potential anticancer compounds is mandelalide A (38) from the Algoa Bay ascidian Lissoclinum species.

Purification and biochemical characterisation of a putative sodium channel agonist secreted from the South African Knobbly sea anemone Bunodosoma capense.

Voltage gated ion channels have become a subject of investigation as possible pharmaceutical targets. Research has linked the activity of ion channels directly to anti-inflammatory pathways, energy homeostasis, cancer proliferation and painful diabetic neuropathy. Sea anemones secrete a diverse array of bioactive compounds including potassium and sodium channel toxins. A putative novel sodium channel agonist (molecular mass of 4619.7 Da) with a predicted sequence: CLCNSDGPSV RGNTLSGILW LAGCPSGWHN CKKHKPTIGW CCK was isolated from Bunodosoma capense using a modified stimulation technique to induce the secretion of the neurotoxin rich mucus confirmed by an Artemia nauplii bio-assay. The peptide purification combined size-exclusion and reverse-phase high performance liquid chromatography. A thallium-based ion flux assay confirmed the presence of a sodium channel agonist/inhibitor and purity was determined using a modified tricine SDS-PAGE system. The peptide isolated indicated the presence of multiple disulfide bonds in a tight ß-defensin cystine conformation. An IC50 value of 26 nM was determined for total channel inhibition on MCF-7 cells. The unique putative sodium channel agonist initiating with a cystine bond indicates a divergent evolution to those previously isolated from Bunodosoma species.

Molecular Networking Reveals Two Distinct Chemotypes in Pyrroloiminoquinone-Producing Tsitsikamma favus Sponges.

The temperate marine sponge, Tsitsikamma favus, produces pyrroloiminoquinone alkaloids with potential as anticancer drug leads. We profiled the secondary metabolite reservoir of T. favus sponges using HR-ESI-LC-MS/MS-based molecular networking analysis followed by preparative purification efforts to map the diversity of new and known pyrroloiminoquinones and related compounds in extracts of seven specimens. Molecular taxonomic identification confirmed all sponges as T. favus and five specimens (chemotype I) were found to produce mainly discorhabdins and tsitsikammamines. Remarkably, however, two specimens (chemotype II) exhibited distinct morphological and chemical characteristics: the absence of discorhabdins, only trace levels of tsitsikammamines and, instead, an abundance of unbranched and halogenated makaluvamines. Targeted chromatographic isolation provided the new makaluvamine Q, the known makaluvamines A and I, tsitsikammamine B, 14-bromo-7,8-dehydro-3-dihydro-discorhabdin C, and the related pyrrolo-ortho-quinones makaluvamine O and makaluvone. Purified compounds displayed different activity profiles in assays for topoisomerase I inhibition, DNA intercalation and antimetabolic activity against human cell lines. This is the first report of makaluvamines from a Tsitsikamma sponge species, and the first description of distinct chemotypes within a species of the Latrunculiidae family. This study sheds new light on the putative pyrroloiminoquinone biosynthetic pathway of latrunculid sponges.

New polyhydroxylated sterols from Palythoa tuberculosa and their apoptotic activity in cancer cells.

The chemical study on the total extract of the zoanthid Palythoa tuberculosa, collected from the Red Sea, resulted in the isolation of seven polyhydroxylated sterols (1-7), six of which, palysterols A-F (2-7), are new. Their chemical structures were elucidated on the basis of extensive analysis of their 1-, 2D NMR and MS spectroscopic data. This is the first chemical investigation on the species collected from Red Sea. We studied the cytotoxic effects of the total extract and some of the new polyhydroxylated sterols in three human cancer cell lines (MCF-7, HeLa, and HT-29) and one non-cancerous human cell line (KMST-6). Palysterol F (7), in particular, was able to selectively induce high levels of apoptosis (>75%) in breast adenocarcinoma (MCF-7) cells but not HeLa, HT-29 and KMST-6 cells.

Mandelalides A-D, cytotoxic macrolides from a new Lissoclinum species of South African tunicate.

Mandelalides A-D are variously glycosylated, unusual polyketide macrolides isolated from a new species of Lissoclinum ascidian collected from South Africa, Algoa Bay near Port Elizabeth and the surrounding Nelson Mandela Metropole. Their planar structures were elucidated on submilligram samples by comprehensive analysis of 1D and 2D NMR data, supported by mass spectrometry. The assignment of relative configuration was accomplished by consideration of homonuclear and heteronuclear coupling constants in tandem with ROESY data. The absolute configuration was assigned for mandelalide A after chiral GC-MS analysis of the hydrolyzed monosaccharide (2-O-methyl-α-L-rhamnose) and consideration of ROESY correlations between the monosaccharide and aglycone in the intact natural product. The resultant absolute configuration of the mandelalide A macrolide was extrapolated to propose the absolute configurations of mandelalides B-D. Remarkably, mandelalide B contained the C-4' epimeric 2-O-methyl-6-dehydro-α-L-talose. Mandelalides A and B showed potent cytotoxicity to human NCI-H460 lung cancer cells (IC(50), 12 and 44 nM, respectively) and mouse Neuro-2A neuroblastoma cells (IC(50), 29 and 84 nM, respectively).