Brent R. Copp

Biomedical Potential of Marine Natural Products

Marine natural products, the secondary or nonprimary metabolites produced by organisms that live in the sea, have received increasing attention from chemists and pharmacologists during the last two decades. Interest on the part of chemists has been twofold: natural products chemists have probed marine organisms as sources of new and unusual organic molecules, while synthetic chemists have followed by targeting these novel structures for development of new analogs and new synthetic methodologies and strategies (Albizati et al., 1990). The rationale for investigating the chemistry of marine organisms has changed over the past several decades. Early investigations were largely of a “phytochemical” nature, reporting detailed metabolite profiles similar to those reported for terrestrial plants in previous decades. However, analogous to investigations of terrestrial plants, more recent studies of marine organisms have focused on their potential applications, particularly to the treatment of human disease and control of agricultural pests (Fautin, 1988). Pharmacological evaluations of marine natural products have likewise undergone an evolution over the past two decades: beginning with the early investigations of toxins, followed by studies of cytotoxic and antitumor activity, to the present day, where a myriad of activities based on whole-animal models and receptor-binding assays are being pursued. The intent of this chapter is to look back at the evolution of biomedically oriented natural product studies of marine organisms, to chronicle the key developments, discoveries, and advances in the level of sophistication that have fueled further interest in this field, and finally to look forward at the future biomedical potential of marine natural products.

Natural product growth inhibitors of Mycobacterium tuberculosis

This review covers natural products (secondary metabolites) with reported growth inhibitory activity towards Mycobacterium tuberculosis or related organisms. Such compounds have been isolated from a variety of sources including terrestrial and marine plants and animals, and microorganisms, with the express intent of identifying novel scaffolds for the development of new antituberculosis agents. The literature from January 2003 to December 2005 (inclusive) is reviewed and 146 references to 353 compounds are cited. The compounds are presented in order of chemical type, namely lipids/fatty acids and simple aromatics, phenolics and quinones, peptides, alkaloids, terpenes (monoterpenoids, diterpenes, sesquiterpenes and triterpenes), steroids and miscellaneous structures.

Antimycobacterial natural products

This review covers the literature published between January 1990 and December 2002 (inclusive) for natural products with reported antimycobacterial activity, with 248 citations to 352 compounds isolated from both terrestrial and marine sources The compounds are presented in order of chemical type, namely lipids/fatty acids and simple aromatics phenolics and acetogenic quinones, peptides, alkaloids, terpenes (monoterpenoids, diterpenes, sesquiterpenes, sesterterpenes and triterpenes) and steroids.

Chemical discovery and global gene expression analysis in zebrafish.

The zebrafish (Danio rerio) provides an excellent model for studying vertebrate development and human disease because of its ex utero, optically transparent embryogenesis and amenability to in vivo manipulation. The rapid embryonic developmental cycle, large clutch sizes and ease of maintenance at large numbers also add to the appeal of this species. Considerable genomic data has recently become publicly available that is aiding the construction of zebrafish microarrays, thus permitting global gene expression analysis. The zebrafish is also suitable for chemical genomics, in part as a result of the permeability of its embryos to small molecules and consequent avoidance of external confounding maternal effects. Finally, there is increasing characterization and analysis of zebrafish models of human disease. Thus, the zebrafish offers a high-quality, high-throughput bioassay tool for determining the biological effect of small molecules as well as for dissecting biological pathways.

Review: Marine natural products

Covering: 2010. Previous review: Nat. Prod. Rep., 2011, 28, 196. This review covers the literature published in 2010 for marine natural products, with 895 citations (590 for the period January to December 2010) referring to compounds isolated from marine microorganisms and phytoplankton, green, brown and red algae, sponges, cnidarians, bryozoans, molluscs, tunicates, echinoderms, mangroves and other intertidal plants and microorganisms. The emphasis is on new compounds (1003 for 2010), together with the relevant biological activities, source organisms and country of origin. Biosynthetic studies, first syntheses, and syntheses that lead to the revision of structures or stereochemistries, have been included.

Pyrroloiminoquinone and related metabolites from marine sponges

This review presents the structure, biological activity, biosynthetic studies and, where applicable, references to syntheses of 81 marine alkaloids containing either tetra-, hexa- or octa-hydrogenated variants of pyrrolo[4,3,2-de]quinoline, pyrrolo[4,3,2-de]pyrrolo[2,3-h]quinoline and pyrido[2,3-h]pyrrolo[4,3,2-de]quinoline core skeletons. The literature describing the isolation of pyrroloiminoquinones, and related metabolites, from marine sponges is littered with taxonomic inconsistencies and recent efforts to clarify the taxonomy of the sponges that produce this group of metabolites are discussed.

Structural requirements for biological activity of the marine alkaloid ascididemin

Comparison of the biological activities observed for ascididemin (2) and synthetic precursors/analogs has established the importance of N-8 in ring A, and a completed ring E, to topoisomerase II enzyme inhibition, human tumor cytotoxicity and antifungal/antibacterial properties. The results also suggest the presence of multiple mechanisms of toxicity by 2 towards mammalian cell systems.

Didemnidines A and B, Indole Spermidine Alkaloids from the New Zealand Ascidian Didemnum sp.

Two new indole spermidine alkaloids, didemnidines A (1) and B (2), have been isolated from the New Zealand ascidian Didemnum sp. The structures of the metabolites, determined by analysis of 2D NMR spectra and confirmed via synthesis, embody an indole-3-glyoxylamide moiety linked to the N(1) position of spermidine, the latter motif being particularly rare among marine natural products. Didemnidine B and a synthetic precursor exhibited mild in vitro growth inhibition of Plasmodium falciparum with IC(50)s of 15 and 8.4 μM, respectively.

Rossinones A and B, Biologically Active Meroterpenoids from the Antarctic Ascidian, Aplidium species

Rossinones A (1) and B (2), biologically active meroterpene derivatives, were isolated from an Antarctic collection of the ascidian Aplidium species and structurally characterized with spectroscopic methods. The absolute configuration of 1 was deduced by using the modified Mosher method. The rossinones exhibit anti-inflammatory, antiviral and antiproliferative activities.

A biologically active 1,2,3-trithiane derivative from the New Zealand ascidain Aplidium sp. D.

cis -5-Hydroxy-4-(4′-hydroxy-3′-methoxyphenyl)-4-(2″-imidazolyl)-1,2,3-trithiane 1 was isolated from the New Zealand ascidian Aplidium sp. D. In neutral or slightly basic solution 1 interconverts to the trans isomer 3 . These isomers are the precursors to 2-vanilloyl imidazole 2 , previously reported from an extract of an Australian species of Aplidium . Both trithiane isomers are active against P388 leukemia cells in vitro .