Interleukin inflammatory inhibitors

One of the invertebrates collected during the 1994 SIO-RU-SKB collaborative marine invertebrate collection from the Aliwal Shoal off southern Kwazulu-Natal, South Africa was the ascidian Lissoclinum sp.. Bioassay guided fractionation of a methanol extract of this ascidian yielded a novel interleukin-8 inhibitor, lissoclin disulfoxide (88) [84], Interleukin-8 (IL-8), a promoter of neutrophil aggregation and activation, is implicated in a wide range of inflammatory disorders e.g. psoriasis and rheumatoid arthritis [85]. In addition to its potent inhibition of both IL-8 Roc and IL-8 R(3 (IC50 = 0.6 and 0.82 pM respectively) 88 also exhibited activity against the protein kinase C enzyme (IC50 = 1.54 pM) [84]. 

A number of adipokines are linked to inflammation and immunity (Fig. 1). This includes both leptin and adiponectin, and also a number of other key inflammatory proteins, particularly cytokines and chemokines [1]. The cytokines and chemokines encompass interleukin-1(3 (EL-1 (3), IL-6, DL-10, TNFa, monocyte chemoattractant protein-1 (MCP-1), and macrophage migration inhibitory factor (MIF). Other major inflammation-related adipokines include nerve growth factor (NGF), and acute phase proteins such as serum amyloid A and haptoglobin. In addition, adipocytes secrete plasminogen activator inhibitor-1 (PAI-1), which is an important thrombotic factor as well as an acute phase protein. 

The anti-inflammatory activity of the NSAIDs is mediated chiefly through inhibition of biosynthesis of prostaglandins (Figure 36-2). Various NSAIDs have additional possible mechanisms of action, including inhibition of chemotaxis, down-regulation of interleukin-1 production, decreased production of free radicals and superoxide, and interference with calcium-mediated intracellular events. Aspirin irreversibly acetylates and blocks platelet cyclooxygenase, while most non-COX-selective NSAIDs are reversible inhibitors. 

Cytokines and antagonists (2—4), intercellular proteins produced by immune cells, play an important role in the regulation of immune responses. Cytokines are present in a variety of tissues under normal conditions. Through insufficient or excessive production, these macromolecules can mediate chronic inflammatory diseases. An inability to respond to cytokines, eg, interleukin 1 (IL-1) or interleukin 2 (IL-2), may lead to an immunosuppressive state, whereas over-production can result in severe shock, autoimmune disease, or immunopathological conditions, such as leukemia and rheumatoid arthritis (RA). Specific communications between immune cells are constantly modulated by naturally occurring inhibitors. 

V,/V-Dimethylaminomethyl-2,3,3 ,12 -tetrahydrodibenzo[A/]furo[2,3- /]oxepine derivatives, for example, 145 (X = F, Cl, Br, OMe, etc.), are described as potent anxiolytic agents <2004CPB262, 2005BML2898, 2005FA241>, dibenzo[A/]thieno[2,3- /]oxepine derivatives are claimed as inhibitors of tumor necrosis factor-cr and interleukin-1 production for the treatment of inflammatory diseases <2004W02004078763>. 8-Oxa-l,2-diazadibenzo[i , ]azulene derivatives (dibenzo[/>,/]pyrazolo[3,4- /]oxepines) were synthesized as inhibitors of tumor necrosis factor-x and interleukin-1 production <2003W02003099822>. 

Peptidomimetic modifications of the tet-rapeptide sequence have led to the conforma-tionally constrained compound (69)as a selective inhibitor of caspase-1 or interleukin-1 converting enzyme (ICE) as potential anti-inflammatory compounds (131). Recently, new non-peptide peptidomimetic diphenyl ether sulfonamides have been described as novel lead structures (70) (Fig. 15.32) (132). 

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