Of great importance to man is the control of pathological cellular proliferation such as that which occurs in the case of cancer. Considerable research and resources have been devoted to oncology and antitumor measures including chemotherapy. While certain methods and chemical compositions have been developed which aid in inhibiting, remitting, or controlling the growth of, for example, tumors, new methods and antitumor chemical compositions are needed. Anti-proliferative agents can also be useful in treating autoimmune diseases and inflammatory disease.
In searching for new biologically active compounds, it has been found that some natural products and organisms are potential sources for chemical molecules having useful biological activity of great diversity. For example, the diterpene commonly known as paclitaxel, isolated from several species of yew trees, is a mitotic spindle poison that stabilizes microtubules and inhibits their depolymerization to free tubulin (Fuchs, D. A., R. K. Johnson [1978] Cancer Treat. Rep. 62:1219-1222; Schiff, P. B., J. Fant, S. B. Horwitz [1979] Nature (London) 22:665-667). Paclitaxel is also known to have antitumor activity and has undergone a number of clinical trials which have shown it to be effective in the treatment of a wide range of cancers (Rowinski, E. K. R. C. Donehower [1995] N. Engl. J. Med. 332:1004-1014). See also, e.g., U.S. Pat. Nos. 5,157,049; 4,960,790; and 4,206,221.
Marine soft corals have also proven to be a source of biologically active chemical molecules. A number of publications disclose organic compounds derived from marine soft corals including Scheuer, P. J. (ed.) Marine Natural Products, Chemical and Biological Perspectives, Academic Press, New York, 1978-1983, Vol. I-V; Faulkner, D. J. (2002) Nat. Prod. Rep. 19:1-48; Faulkner, D. J. Nat Prod Rep. (2001)18:1-49; Faulkner, D. J. (2000); Nat. Prod. Rep 17:7-55; Long B H, Carboni J M, Wasserman A J, Cornell L A, Casazza A M, Jensen P R, Lindel T, Fenical W, Fairchild C R. (1998) “Eleutherobin, a novel cytotoxic agent that induces tubulin polymerization, is similar to paclitaxel (Taxol). Cancer Res 58:1111-5. Some species of soft corals have proven to be rich sources of guaiazulene, inderazulene, and related sesquiterpene pigments. For example: guaizulene from the soft coral Euplexaura erecta (Fusetani, N.; Matsunaga, S.; Konosu, S. Experientia 1981, 37, 680-681); 2,3-dihydrolinderazulene, linderazulene and guiazulene from the soft coral Acalycigorgia sp. (Sakemi, S.; Higa, T. Experientia 1987, 43, 624-625; gorgiabisazulene from Acalycigorgia sp. (Ochi, M.; Kataoka, K; Tatsukawa, A.; Kotsuki, H.; Shibata, K.) Chem. Lett. 1993, 2003-2006; Echinofuran from the gorgonian Echinogorgia praelonga (Tanaka, J; Miki, H.; Higa, T.) J. Nat. Prod. 1992, 55, 1522-1524; and 2,2-biguiazulenyl from the gorgonian Calcicorgia granuslosa (Seo, Y.; Rho, J. R.; Geum, N.; Yoon, J. B.; Shin, J. J. Nat. Prod. 1996, 59, 985-986).
The prevention and control of inflammation is also often of great importance for the treatment of humans and animals. Much research has been devoted to development of compounds having anti-inflammatory properties. Certain methods and chemical compositions have been developed which aid in inhibiting or controlling inflammation, but additional anti-inflammatory methods and compositions are needed.
Neuroinflammatory conditions are complex and poorly understood disease processes. Mononuclear-phagocytes become activated in a number of inflammatory conditions, such as neurogenic inflammation, meningitis, septic shock, Down's syndrome, postischemic brain injury, HIV encephalopathy, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis and multiple sclerosis (Mayer, A. M. [1988] Medicina. (B. Aires.) 58:377-385). Present therapies for these and other inflammatory conditions are based on steroids and nonsteroidal anti-inflammatory compositions which are usually associated with a high incidence of unsatisfactory toxicity and poor efficacy (Faden, A. I. and S. Salzman [1992] Trend in Pharmacological Sciences 13:29-35).
Immunomodulation is a developing segment of immunopharmacology. Immunomodulator compounds and compositions, as the name implies, are useful for modulating or regulating immunological functions in animals. Immunomodulators may be immunostimulants for building up immunities to, or initiate healing from, certain diseases and disorders. Conversely, immunomodulators may be immunoinhibitors or immunosuppressors for preventing undesirable immune reactions of the body to foreign materials, or to prevent or ameliorate autoimmune reactions or diseases.
Immunomodulators have been found to be useful for treating systemic autoimmune diseases, such as lupus erythematosus and diabetes, as well as immunodeficiency diseases. Further, immunomodulators may be useful for immunotherapy of cancer or to prevent rejections of foreign organs or other tissues in transplants, e.g., kidney, heart, or bone marrow.
Various immunomodulator compounds have been discovered, including 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 have been found, however, to have undesirable side effects and/or high toxicity. New immunomodulator compounds are therefore needed to provide a wider range of immunomodulator function.