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Targeting Enzymatic Pathways with Marine-Derived Clinical Agents

par Pereira, Renato R.B.;Dasari, Ramesh;Lefranc, Florence ;Kornienko, Alexander;Kiss, Robert ;Gomes, Nelson G M
Référence Natural Products Targeting Clinically Relevant Enzymes, wiley, page (255-275)
Publication Publié, 2017-01

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Résumé :

Significant efforts have been made during the past 50 years to isolate and identify new marine-derived molecules displaying an array of pharmacological properties. Since the majority of the marine-derived clinical agents and candidates are characterized by pleiotropic mechanisms of action, it is not surprising that the pharmacological effects are frequently attributed to interferences in key enzymatic pathways. The discovery of the nucleosides spongouridine and spongothymidine from the Caribbean sponge Cryptotethya crypta provided the basis for the synthesis of several unnatural derivatives, which culminated in the development of cytarabine, the first marine-derived drug. With a slightly modified structure, lurbinectedin anti-cancer profile and molecular mechanisms remain similar to those of its parent compound displaying equivalent anti-tumour efficacy, but with improved pharmacokinetic and pharmacodynamic properties. Analogously to trabectedin, it was also found to interfere with DNA repair mechanisms as well as with the tumour microenvironment through a cytotoxic effect on monocytes and tumour-associated macrophages (TAMs).