Synthetic and natural product approaches to treating maladies with emphasis on inflammation

We have previously demonstrated that the m-terphenyl analog, 1-carboxymethyl-3,5-diphenyl-2-methylbenzene (CDB), is a non-selective inhibitor of cyclooxygenase (COX) which correlates with this compound's ability to inhibit carrageenan-induced edema and adjuvant-induced arthritis in the rat. Herein, a new series of m-terphenyl amines was synthesized and evaluated as a novel class of COX inhibitors. Structure-activity relationships (SAR) were investigated by functional group modification at the para-position of the C-1' and C-2' phenyl substituents on the central aromatic ring.; We further demonstrate the ability of one member of this novel class of COX inhibitors, aniline 6a (ATy), and its nitric oxide-donating prodrug (ATy-SNAP) to inhibit carrageenan-induced edema in the rat in a dose-dependent manner. Interestingly, ATy SNAP maintained the anti-inflammatory properties of ATy with fewer propensities to induce gastrointestinal and cardiovascular toxicity, which are typically associated with the use of non-steroidal anti-inflammatory drugs. We discuss possible pharmacological mechanisms which may account for the activity of these new anti-inflammatory compounds. We also discuss an alternative anti-inflammatory approach that we have pursued, which focuses on interfering with the synthesis of inflammatory neuropeptides such as substance P and calcintonin gene-related peptide.; In addition to combinatorial chemistry, natural products are an important lead for discovering novel medicinals. In fact, many currently used medicinals are either bioactive naturally occurring compounds, or their derivatives. Often, these chemical templates make excellent synthetic starting points for drugs which eventually may bear no structural relationship to their progenitor. Therefore, we also discuss the isolation and characterization of secondary metabolites from Alaskan microorganisms, as well as the biological evaluation of 9-O-methylfusarubin and Muscadine grape skin powder, all in a continuing effort to identify novel pharmacological treatments for inflammatory and neoplastic diseases.