Editorial [Hot Topic: Chemical Approaches to Anti-Inflammatory Discovery (Guest Editor: Balbina J. Plotkin)]

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.