1. Field of the Invention
The invention relates to novel compounds from a soft coral. Said compounds from the soft coral have ability to inhibit the expression of inducible nitric oxide synthase (iNOS) and/or cyclooxygenase-2 (COX-2).
2. Description of the Related Art
With the progression of civilization, we human beings not only have longevity, but also emphasize the quality of our daily lives. However, a specific and effective drug is still absent for many diseases nowadays, such as cancer, chronic pain and atherosclerosis.
Inflammation has been proven to play an important role in the occurrence of several diseases in many studies. The occurrence of the inflammation-related diseases is highly associated with chronic and long-term inflammation induced by free radicals, pollution, food, ages, and pressure.
Atherosclerosis leads to remold a blood vessel and further causes the reduction of the inside diameter of the vessel. Therefore, it is an important risk factor of one of the leading causes of death, acute and lethal cardiovascular diseases, such as myocardial infarction, stroke and peripheral vascular diseases (Libby, Am J Clin Nutr 83:456S-460S, 2006). Atherosclerosis is proven to be a chronic inflammatory cardiovascular disease (Ross, N Engl J Med 340: 115-126, 1999). When intima cells of the blood vessel are pressed or injured, monocytes are induced to differentiate into macrophages and accumulate abundantly around the injured tissue. Through a series of inflammatory reactions, smooth muscle cells of the blood vessel proliferate and inflammatory cells accumulate, and such reactions damage the blood flow and lead to cardiovascular diseases finally (Lucas and Greaves, Exp Rev Mol Med 3:1-18, 2001; Gordon, Bioassays 17:977-986, 1995;). In animal model studies, the inflammatory critical factors of inducible nitric oxide synthase and cyclooxygenase-2 are shown to play an important role in atherosclerosis (Cipollone, Lupus 14:756-759, 2005; Boyle, Curr Vasc Pharmacol 3:63-68, 2005). Furthermore, bulk of inducible nitric oxide synthase and cyclooxygenase-2 is expressed in the human atherosclerosis tissue that comprises macrophages and proliferated smooth muscle cells (Baker et al, Arterioscler Thromb Vasc Biol 19:646-655, 1999; Buttery et al, Lab Invest 75:77-85, 1996). Presently, inducible nitric oxide synthase and cyclooxygenase-2 inhibitors are proven to significantly prevent the occurrence of atherosclerosis (Burleigh et al, Circulation 105:1816-23, 2002; Hayashi et al, Atherosclerosis 187:316-324, 2006; Osiecki, Altern Med Rev. 9: 32-53, 2004).
According to the definition made by International Association for the Study of Pain (IASP), pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. With the extension of longevity, the opportunities and duration of pain are raised. To estimate in the conservative way, the global anodyne consumption reaches around one hundred billion US dollars. Improving life quality through pain control is an important subject. Among various pains, the factors of neuropathic pain are diverse, such as reduced distal circulation due to diabetes mellitus, neuron damage due to amputation or injury, viral infection and unknown reasons. Clinically, anodynes are divided into addictive anodynes and non-addictive anodynes. The addictive anodyne mainly comprises opiate, but the effect thereof to neuropathic pain is not satisfactory. The non-addictive anodyne comprises a steroid type and a non-steroid type. The steroid anodyne relives pain mainly through an anti-inflammatory pathway. However, the steroid anodyne is nonspecific, and the side effects are significant. The long-term usage is prohibited. On the other hand, the non-steroid anodyne comprises a pain-relieving type (such as panadol) and an anti-inflammatory type (such as aspirin). A non-steroid anti-inflammatory drug (NSAID) is now known to be safe with fewer side effects. The mechanism of a specific NSAID is through inhibiting inducible nitric oxide synthase and cyclooxygenase-2 pathways to relieve pain (Turini and DuBois, Annual Rev Med 53:35, 2002; Handy et al, Br J Pharmacol 123:1119-1126, 1998; Osborne et al, Br J Pharmacol 126:1840-1846, 1999). The product of NO or PGE2 catalyzed by inducible nitric oxide synthase or cyclooxygenase-2 is shown to be critical to the occurrence, maintenance and sensitivity of pain in the central neural system and periphery tissues (Moalem and Tracey, Brain Res Rev 51:240-264, 2006). Compared to using nerve blockers for pain relieving, administering inducible nitric oxide synthase and cyclooxygenase-2 inhibitors does not affect movement and neuron. Therefore, it is an important aspect for drug development.
Recently, many eunicellin-type compounds with a bioactivity had been isolated from the soft corals, such as spp. of Astrogorgia (Fusetani et al., Tetrahedron Lett., 30:7079-7082, 1989), Cladiella (Yamada et al., J. Nat. Prod., 60:393-396, 1997; Ahmed et al., J. Nat. Prod., 68:1051-1055, 2005), Briareum (Ospina and Rodriguez, J. Nat. Prod., 69:1721-1727, 2006), Eunicella (Ortega et al., J. Nat. Prod., 60:485-487, 1997), Litophyton (Miyamoto et al., J. Nat. Prod., 57:1212-1219, 1994), Pachyclavularia (Wang et al., Tetrahedron Lett., 42:2333-2336, 2001), Sclerophytum (Sharma and Alam, J. Chem. Soc., Perkin Trans. 1, 2537-2540, 1988). Soft coral is a possible resource of novel compounds.
USPTO Backgrounds
USPTO Backgrounds