Structural Modification of the Protozoan Toxin Climacostol for Biotechnological Applications

Climacostol (5-[(2Z)-non-2-en-1-yl]benzene-1,3-diol) is a resorcinolic lipid produced by the fresh-water ciliate Climacostomum virens for chemical defense against predators. The new diastereoselective chemical synthesis of the toxin allowed us to test the antimicrobial activity of climacostol as well as its cytotoxic and pro-apoptotic effects in multiple human and rodent tumor cell, with promising results. In this study, we synthesized some novel analogues of climacostol, in order to increase the activity of the native toxin, and evaluated their effects on prokaryotic and eukaryotic microorganisms, as well as on mammalian tumor cell lines. The data collected demonstrate that the introduction of a methyl or a hydroxyl moiety to the aromatic ring of climacostol can effectively regulate both its biological activity and its mechanism of action. In addition, the choice of phenol group protection based on the methoxymethyl ether (MOM), which can easily be removed in weakly acidic environment, allowed us to synthesize a great amount of climacostol in Z-configuration, the most biologically active form. This prompted us to use the non-toxic MOM-protected molecule directly in toxicity tests, in order to identify a new strategy for the generation of efficient small organic molecules as pharmacologically active agents.