Pateamine A (patA) was first isolated from the marine sponge Mycale found off the shores of New Zealand. The natural form bears a thiazole and an E,Z-dienoate within a 19-membered macrocycle and a trienylamine side chain. Two additional pateamines, pateamines B and C, were also isolated. Their structures differ from pateamine A only in the nature of the terminal group of the trienylamine side chain. The basic structure for these three isolated natural forms is shown below.

Isolated pateamine A (native pateamine A) is a novel marine product that promises to be quite useful as a biochemical probe and which displays potent immunosuppressive properties with low cytotoxicity. In MLR (mixed lymphocyte reaction) assay, IC50=2.6 nM while the LCV (lymphocyte viability assay)/MLR ratio is >1000. In comparing native pateamine A to cyclosporin A in a mouse skin graft rejection assay, native pateamine A resulted in a 15-day survival period as opposed to cyclosporin A having only a 10-day survival of the skin graft. Additionally, at high doses, toxicity was at 17% in these studies. For other dose levels, there was no toxicity. All doses were active.
It has also been found that native pateamine A specifically inhibits an intracellular step of the T-cell receptor signal transduction pathway leading to IL-2 transcription. Two syntheses of native pateamine A have been reported. The utility of these molecules as an immunosuppressant or immunostimulant is severely restricted because the molecule lacks stability. Additionally, natural sources of the molecule are limited. Thus, continuous development of synthetic pateamine derivatives having the same or lower toxicity, potent activity and increased stability is required.
Potent activity of native pateamine A in a mixed lymphocyte reaction and also in a mouse skin graft rejection assay have been observed. Native pateamine A originally showed activity in a mixed lymphocyte reaction, (IC50 2.6 nM) and in the mouse skin graft rejection assay. Native pateamine A was found to be more potent than cyclosporin A with only low toxicity at high doses but all doses were active. Native pateamine A may also inhibit a specific intracellular signaling pathway involved in T cell receptor-mediated IL-2 production. In addition to its effect on TCR signaling pathway, native pateamine A has been found to induce apoptosis in certain mammalian cell lines, especially those that are transformed with the oncogene Ras.
Analysis of native pateamine A structure reveals a rigid eastern half (C6-C24) including the thiazole, dienoate, and the triene sidechain, due to extended conjugation, and a more flexible western half (C1-C5). Furthermore, C3-Boc-PatA was found to have only 3-4 fold lower activity than native pateamine A.
Natural products have proven to be extremely useful as probes of biological processes. Examples include the immunosuppressive, microbial secondary metabolites, cyclosporin A, FK506, and rapamycin. Marine organisms have also been a rich source of bioactive compounds, which are proving useful as drug leads and biological probes. For example, bryostatin, epithilone, discodermolide and ecteinascidin show great potential as anti-cancer agents and have revealed novel biological mechanisms of action.
Immunomodulators are useful for treating systemic autoimmune diseases, such as lupus erythematosus and diabetes, as well as immunodeficiency diseases. Immunomodulators are also useful for immunotherapy of cancer or to prevent rejections of foreign organs or other tissues in transplants, e.g., kidney, heart, or bone marrow. Examples of immunomodulators include: FK506, muramylic acid dipeptide derivatives, levamisole, niridazole, oxysuran, flagyl, and others from the groups of interferons, interleukins, leukotrienes, corticosteroids, and cyclosporins. Many of these compounds, however, have undesirable side effects and/or high toxicity in a subject in need thereof. New immunomodulator compounds are, therefore, needed to provide a wider range of immunomodulator function for specific areas with a minimum of undesirable side effects.
Unfortunately, many immunomodulators available currently have undesirable side effects and/or high toxicity and are often difficult to synthesize in pharmacologically effective amounts. What is needed is one or more immunomodulative compounds that may be synthetically produced in effective amounts and provide a broad spectrum of activity (e.g., immunomodulator function) with increased stability and with less undesirable side effects.