Background: Caribbean gorgonians (o. Gorgonacea, Ph. Cnidaria) are a diverse group of marine soft corals that are commonly known as sea whips and sea fans. A wide variety of Caribbean gorgonians are found in great abundance in the shallow water reefs of the West Indian region. Beginning in the 1980's, a group of faculty and graduate students from the University of California along with participants from other institutions began an exploratory field research sampling of soft coral populations at many locations and habitats throughout the West Indies. Extracts were prepared on board ship and preliminary biological testing of extracts carried out. Their chemical components were subsequently found to be a significant source of many diverse organic substances including steroids, prostaglandins, lactones, sesquiterpenoid derivatives, and diterpenoid metabolites. Some of these purified extracts were found to contain previously unknown chemical structures and others contained dimeric and polymeric forms in remarkable complexity; still others were metabolites of closely related animal or plant metabolites and hormones.

A number of Caribbean gorgonians were studied in depth to characterize their chemical structures and biological properties. These studies were carried out as part of a joint research effort between groups at the Scripps Institute for Oceanography/University of California, San Diego and the graduate marine pharmacology group headed by Principal Investigator Robert Jacobs of the Marine Science Institute/University of California, Santa Barbara. One of the truly novel compounds isolated and characterized was pseudopterosin A (PsA; 1). PsA is a tricarbocyclic diterpene glycoside that was found to be a potent topical and systemic anti-inflammatory agent. This drug along with manoalide, a sponge metabolite and the first potent PLA2 inhibitor, became the focus of considerable scientific discussion and increased interest within the biomedical community in these marine natural products in particular and the potential of this resource in general.

Hypothesis: Severe injury from chemical or physical sources continues to be a serious and challenging medical problem from the perspective of successful treatment, survival, and recovery. A physical surface injury to the skin of most animals initiates a complex series of immune and physiological responses involving pain, inflammation, wound repair and scar formation. The total process of wound repair or wound healing is not homogeneous among species but many components of the response are phylogenetically conserved and are observed in very primitive unicellular algae and ciliates.

In vertebrates including man certain forms of injury are followed by a major initial infiltration and concentration of neutrophils at the sight of injury. During the early stages of phagocytosis, these cells degranulate and release stored enzymes such as myeloperoxidase, proteases, lipases, and pro-inflammatory eicosanoids and chemotactic factors that attract additional immune cells. They also produce reactive oxygen species, alter vascular permeability, and induce swelling. Mast cells also contribute to this early stage by releasing histamine and other autocoids.

Relevance: We hypothesize that donor sites in patients undergoing repeated reconstructive surgery may represent a clinical condition that can be simulated experimentally by topical treatment of mouse ears with the irritant phorbol myristate acetate (PMA). We base our hypothesis on the fact that Pseudopterosin A and its analogs block infiltration of neutrophils in the PMA-treated mouse ear and also block phagocytosis and degranulation in cell culture models. Recent Phase 2 clinical trials have shown that topical application of pseudopterosin A methyl ether significantly increased healing rate of donor sites in burn patients. We believe this may be in part the result of diminished pro-inflammatory mediators at the wound site. We wish to exploit these results and propose to optimize the potency and efficacy of the pseudopterosin pharmacophore, increase its bioavailability, and provide a new molecule that can be readily synthesized.