[structure: see text] Chemical investigation of two field collections of marine cyanobacteria has led to the discovery of two new cytotoxic natural products, ankaraholides A (2) and B (3), along with the known compound swinholide A (1). Since swinholide-type compounds were previously localized to the heterotrophic bacteria of sponges, these findings raise intriguing questions about their true metabolic source.
The chemical and biological diversity of the marine environment is immeasurable and therefore is an extraordinary resource for the discovery of new anticancer drugs. Recent technological and methodologic advances in structure elucidation, organic synthesis, and biological assay have resulted in the isolation and clinical evaluation of various novel anticancer agents. These compounds range in structural class from simple linear peptides, such as dolastatin 10, to complex macrocyclic polyethers, such as halichondrin B; equally as diverse are the molecular modes of action by which these molecules impart their biological activity. This review highlights several marine natural products and their synthetic derivatives that are currently undergoing clinical evaluation as anticancer drugs.
Tanikolide seco acid 2 and tanikolide dimer 3, the latter a novel and selective SIRT2 inhibitor, were isolated from the Madagascar marine cyanobacterium Lyngbya majuscula. The structure of 2, isolated as the pure R enantiomer, was elucidated by an X-ray experiment in conjunction with NMR and optical rotation data, whereas the depside molecular structure of 3 was initially thought to be a meso compound as established by NMR, MS and chiral HPLC analyses. Subsequent total synthesis of the three tanikolide dimer stereoisomers 4, 5, and ent-5, followed by chiral GC-MS comparisons with the natural product, showed it to be exclusively the R,R-isomer 5. Tanikolide dimer 3 (=5) inhibited SIRT2 with an IC50 = 176 nM in one assay format, and 2.4 µM in another. Stereochemical determination of symmetrical dimers such as compound 3 pose intriguing and subtle questions in structure elucidation, and as shown in the current work, are perhaps best answered in conjunction with total synthesis.
Two monogalactosyl diacylglycerols, 1 and 2, were isolated from the marine diatom Phaeodactylum tricornutum, using the patented ApopScreen cell-based screen for apoptosis-inducing, potential anticancer compounds. The molecular structures of the galactolipids were determined using a combination of NMR, mass spectrometry, and chemical degradation. The bioactivities were confirmed using a specific apoptosis induction assay based on genetically engineered mammalian cell lines with differential, defined capacities for apoptosis. The galactolipids induce apoptosis in micromolar concentrations. This is the first report of apoptosis induction by galactolipids.The oceans are the largest ecosystem of Earth and hold great, unexplored potential for drug discovery. One of the most important photosynthetic eukaryotes in marine ecosystems are the diatoms, 1 single-celled algae surrounded by a silica-derived wall. There are estimated to bẽ 10 6 species of diatoms, 2,3 which makes them ~4-fold more diverse than angiosperms. These organisms rose to ecological prominence over the past 40 million years, and in part, their success has been attributed not only to efficient resource acquisition strategies but also to allelochemical production that may favor their selection over competitors. Hence, we examined whether this group of organisms produces novel compounds capable of inducing apoptosis.The screening of organic extracts from marine algae and cyanobacteria for mechanism-based anticancer agents has become increasingly efficient and has led to the discovery of new chemotypes showing antiproliferative properties. 4,5 Cytotoxic chemo-therapeutics currently in use for the treatment of cancer rely on the ability to selectively target proliferating cells, which are enriched in tumors. Tumor cells progressively evolve genetic mutations that enable not only cell proliferation but also resistance to apoptosis, a cell suicide pathway that is the cellular response to oncogene activation or irreparable cellular damage. 6-9 Effective cancer therapeutic strategies often rely on preferential and efficient induction of apoptosis in tumor cells. Progressive exposure to such molecules commonly leads to selection of resistant cells that are therapeutically associated with both tumor progression and resistance to chemotherapy. [6][7][8][9] While many conventional cytotoxic chemotherapeutics trigger apoptosis indirectly by inflicting cellular damage, recent efforts have been directed to developing agents that specifically target or activate a caspase cascade that leads to apoptosis. 10In our ongoing effort to discover and develop new marine natural product biomedicinals, we have screened extracts from several marine organisms and have found that those isolated from a cultured marine diatom, Phaeodactylum tricornutum, possessed an ability to specifically induce apoptosis in immortal mammalian epithelial cells. Subsequently, extracts were subjected to ApopScreen bioas-say-guided purification, which resulted in the isolation of two monogalactos...
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