Coral reefs are among the most productive marine ecosystems and are the source of a large group of structurally unique biosynthetic products. Annual reviews of marine natural products continue to illustrate that the most prolific source of bioactive compounds consist of coral reef invertebrates—sponges, ascidians, mollusks, and bryozoans. This account examines recent milestone developments pertaining to compounds from invertebrates designated as therapeutic leads for biomedical discovery. The focus is on the secondary metabolites, their inspirational structural scaffolds and the possible role of microorganism associants in their biosynthesis. Also important are the increasing concerns regarding the collection of reef invertebrates for the discovery process. The case examples considered here will be useful to insure that future research to unearth bioactive invertebrate-derived compounds will be carried out in a sustainable and environmentally conscious fashion. Our account begins with some observations pertaining to the natural history of these organisms. Many still believe that a serious obstacle to the ultimate development of a marine natural product isolated from coral reef invertebrates is the problem of compound supply. Recent achievements through total synthesis can now be drawn on to forcefully cast this myth aside. The tools of semisynthesis of complex natural products or insights from SAR efforts to simplify an active pharmacophore are at hand and demand discussion. Equally exciting is the prospect that invertebrate-associated micro-organisms may represent the next frontier to accelerate the development of high priority therapeutic candidates. Currently in the United States there are two FDA approved marine-derived therapeutic drugs and two others that are often cited as being marine-inspired. This record will be examined first followed by an analysis of a dozen of our favorite examples of coral reef invertebrate natural products having therapeutic potential. The record of using complex scaffolds of marine invertebrate products as the starting point for development will be reviewed by considering eight case examples. The potential promise of developing invertebrate-derived micro-organisms as the starting point for further exploration of therapeutically relevant structures is considered. Also significant is the circumstance that there are some 14 sponge-derived compounds that are available to facilitate fundamental biological investigations.
A nuclear factor-κB (NF-κB) luciferase assay has been employed to identify the bengamides, previously known for their anti-tumor activity, as a new class of immune modulators. A unique element of this study was that the bengamide analogs were isolated from two disparate sources, Myxococcus virescens (bacterium) and Jaspis coriacea (sponge). Comparative LC-MS/ELSD and NMR analysis facilitated the isolation of M. viriscens derived samples of bengamide E (8) and two congeners, bengamide E’ (13) and F’ (14) each isolated as an insperable mixture of diastereomers. Additional compounds drawn from the UC Santa Cruz repository allowed expansion of the structure activity relationship (SAR) studies. The activity patterns observed for bengamide A (6), B (7), E (8), F (9), LAF 389 (12) and 13–14 gave rise to the following observations and conclusions. Compounds 6 and 7 display potent inhibition of NF-κB (at 80 and 90 nM respectively) without cytotoxicity to RAW264.7 macrophage immune cells. Western blot and qPCR analysis indicated that 6 and 7 reduce the phosphorylation of IκBα and the LPS-induced expression of the pro-inflammatory cytokines/chemokines TNFα, IL-6 and MCP-1 but do not effect NO production or the expression of iNOS. These results suggest that the bengamides may serve as therapeutic leads for the treatment of diseases involving inflammation, that their anti-tumor activity can in part be attributed to their ability to serve as immune modulating agents, and that their therapeutic potential against cancer merits further consideration.
In this chapter we discuss a selection of structurally diverse marine-derived small molecules (MDSMs) with potent and/or specific bioactivity and analyze their biomedical applications. The compounds included have been isolated either from marine macroorganisms, including sponges, ascidians (tunicates), bryozoans, and molluscs, or from microorganisms, such as bacteria and fungi. Our inquiry begins with a look back in time at a selection of important marine natural products, with particular focus on compounds in the clinical pipeline. The chapter continues with an analysis of a biosynthetically diverse assortment of 22 MDSMs and their structural elements of atom and stereochemical diversity. Entries have been divided into five biosynthetic classes: terpene, polyketide, alkaloid, depsipeptide, and polyketide-peptide. Enormous structural variety is represented by the marine natural products treated herein. The compounds selected can be considered to represent case examples of significant biomolecules with positivity and, in some cases, potent bioactivity accompanied by an unusual mechanism of action. Overview of known compounds, highlighting molecules of significanceThe ocean covers more than 70% of the earth's surface and is home to exceptional biodiversity: more than one million marine species and an estimated one billion different kinds of marine microbe (Census of Marine Life Press Release 2010). We and others firmly believe that MDSMs represent a continuing resource for tools important in cell biology research and in the design of the next-generation leads for drug discovery and development. The record to date firmly illustrates that the structures of natural products continue to be invaluable in expanding pharmacophore structural space. For example, Newman and Cragg recently provided a detailed analysis of the last 30 years of natural products in drug discovery, wherein they contended that, "Nature's 'treasure trove of small molecules' remains to be explored, particularly from the marine and microbial environments" (Newman & Cragg 2012).
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