Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Inflammatory and Anti-Allergy Agents) - Volume 6, Issue 4, 2007

The one bullet-one target approach to drug design where compounds exhibit a single specificity in action and function is generally the preferred design. However, there are multiple classes of agents with antiinflammatory activity that are multifunction with activity across taxonomic kingdoms, cell types and molecular targets. The aim of this volume is to examine the structure-function relationship for antiinflammatory agents which exhibit multiple activities. For agents like the tetracyclines, which are bacteriostatic antibiotics, their antiinflammatory activity was a secondary finding. Tetracyclines in addition to inhibiting bacterial protein synthesis, inhibit collagenases, proteolysis, angiogenesis, apoptosis, bone metabolism and modulation of matrix metalloproteinase activity. Based on this ability to inhibit various pro-inflammatory pathways, tetracyclines are being used in the treatment of rheumatoid arthritis, adult periodontal diseases and rosacea. Ethanol, which is used as a bacterial disinfectant/antiseptic/cleanser, is also one of the most commonly self-administered compounds which can modify immune responses. However, these effects of ethanol on the inflammatory response can be opposing depending on dosage; low levels associated with an anti-inflammatory effect and chronic consumption of high levels of ethanol linked to augmentation of inflammatory responses. Sulfur-containing compounds appear to target NF-κB, thus potentially have broad impact on a variety of cellular mechanisms, such as proliferation, differentiation, angiogenesis and metastasis. Also under development are new drugs utilizing thiogold complexes. These compounds have a broad range of clinical targets from cellular (cancer), to viral (AIDS) and parasital (malaria). Other compounds act across phyla as signaling molecules, thus having multiple activities. Salicylate, a signaling molecule in plants, also exhibits similar activity in mammalian cells and microbial cells resulting in antithrombotic, anti-inflammatory, anti-neoplastic, and anti-microbial actions. As with other compounds such as the sulfur-containing compounds, salicylates are active in controlling inflammation and tumor growth by altering gene expression; they inhibit suppress the DNA binding activities of NF-κB, AP-1 and C/EBPβ in a concentration dependent manner which may account for their diverse spectrum of activity. Alternatively, compounds like coumarin reduce tissue edema and inflammation by inhibiting prostaglandin biosynthesis and fatty acid hydroperoxy-intermediates. It is to be expected that coumarin might affect the formation and scavenging of reactive substances derived from oxygen species (ROS) and influence processes involving free radical-mediated injury, as can flavonoids. Similarly, the anti-inflammatory iridoids also showed anti-oxidant, anti-tumor, hepatoprotective, immunomodulatory, antimicrobial, antinociceptive, neuroprotective, neurotogenic, angiogenic, anxiolytic, osteoporotic, and anti-aging activities. Like salicylates, the iridoids have also been part of herbal medicine for generations. Multiple anti-inflammatory activities can also be mediated via various pathways in mammalian cells. This is exemplified by the retinoid story wherein there are both genomic and non-genomic mechanisms which contribute to the pleiotropic effects of retinoids and receptors and exemplify both intracellular and intercellular cross-talk. Thus, retinoids may serve as the paradigm for the multiplicity of sometimes seemingly contradictory activities of this group of antiinflammatory agents.

The tetracyclines are broad-spectrum bacteriostatic antibiotics which interfere with the protein synthesis of bacteria at the ribosomal level. More recently the nonantibiotic properties of tetracyclines have attracted increasing interest. Since the initial observations that tetracyclines inhibit collagenases, extensive number of studies have shown that tetracyclines have effects on inflammation, proteolysis, angiogenesis, apoptosis, and bone metabolism. The mechanism of their action is complex and not completely understood. It includes inhibition of free radical formation and cytokine production, interference with protein synthesis, and modulation of matrix metalloproteinase activity. Chemically modified tetracyclines (CMTs) are tetracycline derivates which lack the antibiotic activity of tetracyclines but possess anti-inflammatory properties. The therapeutic effects of tetracyclines and its analogues have been studied in various inflammatory diseases. Encouraging results have been obtained in the treatment of rheumatoid arthritis (RA) and based on those results minocycline is currently used in the treatment of selected RA patients. Doxycycline has been approved for the treatment of adult periodontal diseases and rosacea. The role of tetracyclines has been studied also in cardiovascular diseases and neuroprotection but their true potential in these diseases remains to be determined. In this review the nonantibiotic properties of tetracycline and its analogues will be examined and their potential for clinical applications in inflammatory diseases will be discussed.

Ethanol (alcohol) consumption can modify immune responses. Moderate ethanol use is associated with lower production of mediators of inflammation and has anti-inflammatory effect, while ethanol abuse and alcoholism are linked with augmentation of inflammatory responses. Ethanol exposure can result in functional alterations of macrophages and other cells of the innate immune system. These cells recognize microbial antigens through Toll-like receptors (TLRs). Molecular mechanisms underlying the inflammatory responses stimulated via TLRs involve activation of intracellular signaling pathways that include mitogen-activated protein kinases (MAPKs) and transcription factor NFκB. Growing evidence indicates that ethanol can affect these cellular events in a manner that depends on the organ or cell type and the pattern of ethanol administration (moderate or acute versus chronic).

Sulfur-containing compounds have proved to be excellent anti-inflammatory agents. In this pharmacological class of compounds the sulfur atom can be found both in reduced and oxidized state. We were interested in outlining the roles of the sulfur moiety and correlate its anti-inflammatory activity to other pharmacological roles based on the mechanism of action of the sulfur groups.

Salicylate is a signaling molecule in plants. It also exhibits signaling activities in mammalian cells. Experimental and clinical data indicate that salicylates have a spectrum of activities, including antithrombotic, anti-inflammatiory, anti-neoplastic, and anti-microbial actions. Aspirin, a synthetic derivative of salicylic acid, is widely used in treating human diseases. The antithrombotic action is unique to aspirin and not shared by other salicylates as only aspirin possesses the property to acetylate COX-1. Other actions of salicylates are attributed to salicylate, a major metabolite of aspirin in vivo. Salicylates are active in controlling inflammation and tumor growth by altering gene expressions. They suppress the expression of pro-inflammatory genes by inhibiting the DNA binding activities of transcription activators such as NF-κB, AP-1 and C/EBPβ. Their actions appear to be concentration related. Salicylates at high concentrations non-selectively inhibit the binding activities of diverse transactivators. At pharmacological concentrations, salicylates inhibit C/EBPβ binding and C-Rel. Transcriptional suppression by salicylates is mediated by kinase inhibition. Salicylates at high concentrations inhibit diverse classes of kinases and, paradoxically, activate some kinases. However, at micromolar concentrations, salicylates inhibit p90 ribosomal S6 kinase (RSK) and p70 S6 kinase (S6K). The mechanism by which salicylates inhibit kinases is unclear. We propose that salicylates at mM concentrations non-selectively inhibit ATP binding to kinases. At micromolar concentrations, they inhibit substrate binding to a selective family of kinases including RSK and S6K. Further structural analysis will yield valuable information which will be useful in designing new anti-inflammatory and antineoplastic drugs.

Inflammation is the primary host defense mechanism against all forms of injury. Excessive or inadequate activation of the system can have serious effects, as can the failure of inactivation mechanisms. Coumarins can reduce tissue edema and inflammation and inhibit prostaglandin biosynthesis, which involves fatty acid hydroperoxy intermediates. It is to be expected that coumarins might affect the formation and scavenging of reactive substances derived from oxygen species (ROS) and influence processes involving free radical-mediated injury, as can flavonoids. During these years a small number of (Q)SAR studies concerning coumarins as NSAIDs has been presented and reviewed. In this research we tried to examine the structure-function relationship for coumarins, presenting antiinflammatory activity. Coumarin (1), the prototypical compound presents anti-inflammatory activity. The hydroxylaromatic substituted derivatives (5- or 6- or 7-hydroxy or the vicinal dihydroxy) seems to be potent inhibitors of lipoxygenase. Several synthetic derivatives simple or more complicated were found to be potent antiinflammatories/antioxidant agents.

Iridoids discussed in this review were chosen based on their anti-inflammatory activity and their having various different bioactivities. Harpagoside is the major iridoid glycoside (0.5-1.6%) in Harpagophytum procumbens, an herbal medicine for rheumatologic conditions. The stem bark of C. ovata is used as an anti-inflammatory drug and catalposide is the main constituent. Geniposide is a main iridoid glucoside of Gardenia jasmoides, 56.2 mg / 500 mg extract. Gardenia fruits are used for the treatment of anti-inflammatory, hepatic and gall bladder diseases. Catalpol, known for its neuroprotective activity, is the major constituent of the roots of Rehmannia glutinosa, which are traditionally used for the treatment of auditory diseases such as tinnitus. Aucubin, which is frequently found as a natural constituent of many traditional medicinal plants, is used in the alleviation of chronic allergic inflammatory disease. PicroLiv, an anti-inflammagen, is a standardized fraction from the root and rhizome of Picrorhiza kurroa containing picrosides I and II and kutkoside. Both aucubin and PicroLiv have potent hepatoprotective activity.

Recent advances have suggested that nongenomic action of retinoids and their receptors represents an important mechanism by which they exert therapeutic effects. Here we review rapid biological responses triggered by retinoids and related molecules by focusing on novel nongenomic mechanisms involving cytoplasmic action of nuclear receptors Nur77 and retinoid X receptor (RXR) in the regulation of apoptosis and inflammation. A class of apoptosis-inducing compounds related to atypical retinoid AHPN/CD437 has emerged as promising therapeutic agents. They rapidly induce mitochondrial targeting of Nur77 and RXR and conversion of Bcl-2 from a cellular protector to a killer. Thus, understanding the nongenomic action of Nur77 and RXR may provide a rational basis to guide the design and development of new therapeutic agents for cancer, and skin, cardiovascular, metabolic and central nervous disorders.