This paper is dedicated to the memory of Prof. Francisco Orallo, who died unexpectedly during the preparation of this manuscript.
In recent years, several studies have proposed the cyclo-oxygenases (COXs) as therapeutic targets in the prevention of cancer. [1] Some epidemiological investigations highlighted that nonsteroidal anti-inflammatory drugs (NSAIDs) reduced the development of several malignant diseases, including colorectal cancer. [2,3,4] NSAIDs inhibit COXs and consequently decrease the levels of prostaglandins (PG) that are significantly involved in carcinogenesis. [5,6] In fact, COX (also known as prostaglandin G/H synthase) is a heme-containing enzyme that catalyzes the conversion of arachidonic acid (AA) into the hydroperoxide prostaglandin G 2 (PGG 2 ) and its subsequent reduction to prostaglandin H 2 (PGH 2 ). PGH 2 is a precursor of several classes of eicosanoids, which modulate central physiological functions, such as the inflammatory response, platelet aggregation, and the protection of gastric mucosa.
Two main COX isoforms are known: the constitutive isoform COX-1 and the inducible isoform COX-2. They show similar catalytic activity and share 65 % amino acid sequence homology. COX-1 is involved in regulating vascular tone, and it is mainly present in the gastrointestinal tract and platelets. Inhibition of COX-1 by NSAIDs is believed to cause the adverse side effects associated with these drugs. Conversely, the COX-2 isoform is normally absent in healthy tissues, but it is rapidly induced in response to inflammatory mediators, such as bacterial endotoxin, interleukin 1 and various growth factors.
The COX active site is a narrow cleft, approximately 8 wide and 25 long. NSAIDs, with the exception of the acetylsalicilic acid, show reversible and competitive COX inhibition. Several scaffolds are able to exert selective COX inhibition, as exempli-fied by indometacin, diclofenac, nimesulide, DuP 697, SC-588 (shown).