Chemistry and biology of anti-inflammatory marine natural products: molecules interfering with cyclooxygenase, NF-κB and other unidentified targets

The majority of the anti-inflammatory drugs routinely used nowadays are COX (cyclo-oxygenase) inhibitors.  The important role of this enzyme, once known as prostaglandin synthase, in inflammation came a consequence of the discovery by the Nobel prize winner John Vane with his path-breaking discovery that aspirin and similar drugs exert their action by blocking the biosynthesis of the prostaglandin group of lipid mediators.  John R. Vane, Nobel Lecture, Dec. 8, 1982 and refs. cited therein, in the last five years it has become clear that there are two such enzymes involved.  One of the "cyclo-oxygenases", called COX1 is responsible for making prostaglandins, which among other things, protect the stomach and kidney from damage.  It is now clear that inhibition of COX1 accounts for the unwanted side effects of aspirin-like drugs such as gastric irritation and renal damage.  The other enzyme, COX2, is induced by inflammatory stimuli and it is prostaglandins made by this enzyme that contribute to the inflammation in diseases such as rheumatoid arthritis.  However, concerning inflammation-related targets, one should not limit the interest to COX and PLA2 enzymes.  In recent years, it has steadily become more clear, that modulation in the expression of genes underlies most cellular responses, and inflammation is certainly not an exception in this sense.  It does not come as surprise that mols. showing ability to interfere with factors involved in the modulation of genes expression, such as NF-κB, have also to be considered potential anti-inflammatory agents.  Also in this respect, marine natural products (MNP) have brought a collection of novel mol. entities displaying ability to target COX1/COX2, NF-κB or acting through mol. mechanisms yet-to-be-discovered.  Following, the marine natural products accounted for within this review will be grouped on the basis of their bio-mol. targets.  Chem. synthesis of particular relevant mols. will be also discussed, esp. in those cases where the natural products can be considered as lead compds. for the development of simplified derivs. or analogs of potential pharmaceutical interest.