NONSTEROIDAL antiinflammatory drugs (NSAIDs) have become an integral part of the therapy of rheumatologic disorders.1 The number of new agents available on the market has more than tripled in the p...

Renal Syndromes Associated with Nonsteroidal Antiinflammatory Drugs

The rate-limiting enzyme in arachidonate metabolism is mediated by enzymes known as cyclooxygenases (COXs), These enzymes catalyze the biosynthesis of prostaglandin H 2 , the precursor of molecules, such as prostaglandins, prostacyclin, and thromboxanes. The COX enzyme family consists of the classical COX-1 enzyme, which is constitutively expressed in many tissues, and a second enzyme, i.e., COX-2, which is induced by various stimuli, such as mitogens and cytokines, and is involved in many inflammatory reactions. Because nonsteroidal anti-inflammatory drugs inhibit both COX-1 and COX-2, these drugs also cause unwanted side effects, exemplified by gastrointestinal bleeding. Accumulating evidence indicates that nonsteroidal anti-inflammatory drugs can reduce the incidence of colorectal cancers in human and experimental animals and can reduce the polyp number and size in patients with familial adenomatous polyposis. This Part I (of a two-part review) focuses on the discovery of the COXs; their biochemical, molecular, and structural properties ; and on the discovery of isozyme-specific inhibitors of COX activity.

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Cyclooxygenase-2 Inhibitors in Tumorigenesis (Part II)

The arachidonic acid cascade generates a family of bioactive lipids that modulate diverse physiological and pathophysiological responses. Although there has been a great deal of interest in the involvement of arachidonic acid metabolites in cancer, there is uncertainty about which metabolites are the most im portant and how they contribute to specific steps in cell trans formation, tumor growth, and metastasis (1-9). The complex ity of arachidonic acid metabolism is daunting to neophytes and the multiplicity of responses exerted by a single metabolite can be confusing to the cognoscenti. This has made it difficult to extrapolate results from animal experiments to human beings. A recent report from Thun et al. (10) and previous reports from Rune et al. (11) and Rosenberg et al. (12) suggest that aspirin intake may reduce colon cancer incidence (11, 12) and mortality (10) in the general population. Other studies from Paganini-Hill et al. (13, 14) do not support such an association. Aspirin is a relatively specific inhibitor of one branch of the arachidonic acid cascade and even though there is not universal agreement among these epidemiological investigations, their findings refocus attention on the role of arachidonic acid me tabolites in cancer. This Perspective was written to highlight some of the existing literature on the aspirin-inhibitable branch of the arachidonic acid cascade and cancer, to apply that liter ature to colon cancer where possible, and to identify deficien cies in our knowledge that need to be addressed. Although the major focus is the colon, the mechanistic concepts should be applicable to other organ sites. The Perspective begins with an overview of arachidonic acid metabolism, proceeds to a consideration of the biochemistry and molecular biology of the enzyme inhibited by aspirin, touches on the signal transduction pathways linked to arachi donic acid metabolism, and then considers mechanisms by which specific arachidonic acid metabolites participate in the carcinogenic process. The review is not meant to be compre hensive and apologies are made in advance to colleagues whose work is not highlighted or was inadvertantly omitted.

/pdf/aspirin-and-the-potential-role-of-prostaglandins-in-colon-149n52w61k.pdf

Aspirin and the Potential Role of Prostaglandins in Colon Cancer

2.5. Ionic Liquids Presented in This Review 2020 3. Cyclocondensation Reactions 2020 4. Synthesis of Three-Membered Heterocycles 2022 4.1. Aziridines 2022 5. Synthesis of Five-Membered Heterocycles 2022 5.1. Pyrroles 2022 5.2. Furans 2022 5.3. Thiophenes 2023 5.4. Pyrazoles 2024 5.5. Imidazoles 2025 5.6. Isoxazoles 2027 5.7. Oxazoles, Oxazolines, and Oxazolidinones 2027 5.8. Thiazoles and Thiazolidinones 2028 6. Synthesis of Six-Membered Heterocycles 2030 6.1. Pyridines 2030 6.2. Quinolines 2031 6.3. Acridines 2033 6.4. Pyrans 2033 6.5. Flavones 2035 6.6. Pyrimidines and Pyrimidinones 2035 6.7. Quinazolines 2037 6.8. -Carbolines 2038 6.9. Dioxanes 2039 6.10. Oxazines 2039 6.11. Benzothiazines 2040 6.12. Triazines 2040 7. Synthesis of Seven-Membered Heterocycles: Diazepines 2041

Ionic liquids in heterocyclic synthesis.

The Methylation Effect in Medicinal Chemistry Eliezer J. Barreiro,* Arthur E. K€ummerle, and Carlos A. M. Fraga Laborat orio de Avaliac-~ao e Síntese de Subst̂ancias Bioativas (LASSBio), Faculdade de Farm acia, Universidade Federal do Rio de Janeiro, CCS, Cidade Universit aria, CP 68.006, 21941-902 Rio de Janeiro, RJ, Brazil Programa de P os-Graduac-~ao em Farmacologia e Química Medicinal, Instituto de Cîencias Biom edicas, Universidade Federal do Rio de Janeiro, Cidade Universit aria, Ilha do Fund~ao, Rio de Janeiro, RJ, Brazil Programa de P os-Graduac-~ao em Química, Instituto de Química, Universidade Federal do Rio de Janeiro, Cidade Universit aria, Ilha do Fund~ao, Rio de Janeiro, RJ, Brazil

Edward H. Wiseman

Papers

Preparation and antiinflammatory activity of some nonacidic trisubstituted imidazoles.

Synthesis and antiinflammatory activity of some 3-carboxamides of 2-alkyl-4-hydroxy-2H-1,2-benzothiazine 1,1-dioxide

Potent anti-inflammatory N-heterocyclic 3-carboxamides of 4-hydroxy-2-methyl-2H-1,2-benzothiazine 1,1-dioxide

Sudoxicam and related N-heterocyclic carboxamides of 4-hydroxy-2H-1,2-benzothiazine 1,1-dioxide. Potent nonsteroidal antiinflammatory agents.

Piroxicam and other anti-inflammatory oxicams