ABSTRACT
Before embarking on a discussion of biologically active natural products from Australian marine organisms, it is useful spending a moment considering the term biologically active, particularly as relates to the interconnecting themes of marine chemical ecology and drug discovery. The reasons are twofold. First, some may question the premise that the chemical ecology achievements of primitive marine creatures could inspire the development of new drugs-particularly drugs applicable to human disease. In response, history has successfully and repeatedly traversed the path from terrestrial plants, animals, and microbes, through traditional medicines to modern pharmacology and therapeutics, so it should come as no surprise that we turn to the marine “road less travelled” in our search for new routes to better drugs. Second, the proposition that
17.1 Introduction ................................................................................................. 579 17.2 Porifera (Sponges) ....................................................................................... 581 17.3 Chordata (Tunicates and Ascidians) ........................................................... 587 17.4 Cnidaria (Soft and Stony Corals) ................................................................ 589 17.5 Bryozoa (Lace Corals) ................................................................................ 589 17.6 Echinodermata (Sea and Feather Stars) ...................................................... 589 17.7 Mollusca (Gastropods, Clams, Siphonaria, Nudibranches,
Octopus, Cone Shells) ..........................................................................591 17.8 Phaeophyta (Brown Algae) ......................................................................... 591 17.9 Rhodophyta (Red Algae)............................................................................. 592 17.10 Chlorophyta (Green Algae) ......................................................................... 593 17.11 Cyanobacteria (Blue-Green Algae) ............................................................. 594 17.12 Marine-Derived Bacteria and Fungi ........................................................... 594 17.13 Past, Present, and Future: A Personal Viewpoint ....................................... 595 References .............................................................................................................. 597
biologically active metabolites have value inevitably implies the corollary view that biologically inactive metabolites have no (or lesser) value. The danger of judging by these criteria is that all too often the assessment of biologically active versus inactive is based on a limited set of bioassays. Choose the wrong bioassay(s) and an exquisitely potent and selective biologically active marine metabolite can be mistakenly categorized and dismissed as inactive. Put another way, simply because we may not currently know or appreciate the biological activity of a particular marine metabolite, it does not mean that it is biologically inactive and thereby lacking in drug discovery potential. But why should we give marine metabolites the bene˜t of the doubt? Surely, if they do not register in the “bioassay of the day,” it is reasonable to assume they are inactive, dismiss them, and move on. The answer, a resounding no, goes to the heart of what natural products are, how they came to exist, and how we might make best use of them. Conventional wisdom has marine natural products providing host organisms with a survival advantage, typically referred to as a chemical defense. The host organisms can themselves be the biosynthetic source of these metabolites, or they can acquire them from dietary sources and/or symbiotic/associated organisms (bacteria or microalgae). These chemicals can protect the host from infection (antibiotics, antiparasitics), repel or dissuade predators (antifeedants, toxins), inhibit the development and growth of competitors (selective cytotoxins and cell growth inhibitors), or even guard against UV radiation (sunscreens). They may also enhance reproductive outcomes (sperm attractants), or improve the ability to feed by rapidly immobilizing prey (venoms). This ecological signi˜cance can on occasion be tested experimentally. For example, a marine algal metabolite that elicits a feeding avoidance response when added to the food pellets of aquaria ˜sh might have an ecological role as an antifeedant against herbivorous reef ˜sh. Similarly, a marine tunicate metabolite that is antibacterial toward laboratory strains of human pathogenic bacteria might protect the tunicate from opportunistic pathogens present in seawater, while a marine sponge metabolite that selectively kills fast growing human cancer cells in tissue culture might inhibit growth and development of the avalanche of larval species that threaten overgrowth of ˜lter feeding organisms such as sponges. That such insights into marine chemical ecology are achieved by proxy in the laboratory is an inevitable consequence of the challenges associated with replicating complex marine ecosystems. Although a number of noteworthy exceptions exist, for the large part we remain ignorant of, or at best hypothesize on, the ecological role played by the vast majority of known marine metabolites. This limitation notwithstanding, as our knowledge of marine metabolites has grown over the last three to four decades to include many thousands of diverse structures from numerous species, it has become clear that these chemicals are disproportionally represented in sedentary or slow moving lineages such as invertebrates and algae. As these life forms typically lack the physical attributes to ´ee (˜ns, legs), ˜ght (claws, spines) or take cover (shells), and include some of the oldest marine life forms, it is little wonder that they have experienced both the selection pressure and time to evolve chemicals to enhance survival. Similarly with marine microbes, which have embraced chemistry to enhance survival and successfully compete for resources in unique niche ecosystems. Under this scenario, all marine metabolites should be viewed as implicitly biologically active within their ecological setting. Such metabolites represent an extraordinary preassembled pool of biologically active molecular diversity, programmed by evolutionary processes to be potent and selective modulators of key
biopolymers (i.e., DNA, proteins, etc.), cells, tissues, organs, and animals. In essence, these metabolites represent Nature’s intellectual property, gleaned from the evolutionary equivalent of a billion year global drug discovery program, boasting an unlimited budget and a workforce of trillions. Clearly a very, very, long-term investment, but one with an impressively successful intellectual property portfolio! The privileged biologically active chemical structures that have emerged from this (ongoing) investment can inform, guide, and inspire modern drug discovery, allowing us to repurpose ecological advantage to pharmaceutical bene˜t. To extend a nautical metaphor,
…Marine metabolites can be viewed as natural “molecular” waypoints, guiding our exploration of the in˜nite reaches of chemical space, serving as both inspiration and compass as we search out the very elusive islands and archipelagos of biological activity, and the even rarer hidden safe harbors of new drugs.
