Chemistry and biology of anti-inflammatory marine natural products: molecules interfering with cyclooxygenase, NF-kappaB 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, December 8, 1982 and references 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 molecules showing ability to interfere with factors involved in the modulation of genes expression, such as NF-kB, have also to be considered potential anti-inflammatory agents. Also in this respect, marine natural products (MNP) have brought a collection of novel molecular entities displaying ability to target COX1/COX2, NF-kappaB or acting through molecular mechanisms yet-to-be-discovered. Following, the marine natural products accounted for within this review will be grouped on the basis of their bio-molecular targets. Chemical synthesis of particular relevant molecules will be also discussed, especially in those cases where the natural products can be considered as lead compounds for the development of simplified derivatives or analogues of potential pharmaceutical interest.
Terracciano
Stefania
S
Dipartimento di Scienze Farmaceutiche, Università di Salerno, Via Ponte Don Melillo, 84084 Fisciano (SA), Italy.
Aquino
Maurizio
M
Rodriquez
Manuela
M
Monti
Maria Chiara
MC
Casapullo
Agostino
A
Riccio
Raffaele
R
Gomez-Paloma
Luigi
L
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D001688:Biological Products / Q000737:chemistry / Q000494:pharmacology*; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008386:Marine Biology; D015394:Molecular Structure; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism*; D010741:Phospholipases A / Q000378:metabolism; D054467:Phospholipases A2; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001688:Biological Products; D016861:Cyclooxygenase Inhibitors; D016328:NF-kappa B; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D010741:Phospholipases A; D054467:Phospholipases A2