Abstract
Climacostol (5-[(2Z)-non-2-en-1-yl]benzene-1,3-diol) is a resorcinol produced by the protozoan Climacostomum virens for defence against predators. It exerts a potent antimicrobial activity against bacterial and fungal pathogens, inhibits the growth of several human and rodent tumour cells, and is now available by chemical synthesis. In this study, we chemically synthesized two novel analogues of climacostol, namely, 2-methyl-5 [(2Z)-non-2-en-1-yl]benzene-1,3-diol (AN1) and 5-[(2Z)-non-2-en-1-yl]benzene-1,2,3-triol (AN2), with the aim to increase the activity of the native toxin, evaluating their effects on prokaryotic and free-living protists and on mammalian tumour cells. The results demonstrated that the analogue bearing a methyl group (AN1) in the aromatic ring exhibited appreciably higher toxicity against pathogen microbes and protists than climacostol. On the other hand, the analogue bearing an additional hydroxyl group (AN2) in the aromatic ring revealed its ability to induce programmed cell death in protistan cells. Overall, the data collected demonstrate that the introduction of a methyl or a hydroxyl moiety to the aromatic ring of climacostol can effectively modulate its potency and its mechanism of action.
Highlights
Natural products possess enormous structural and chemical diversity that is unsurpassed by any synthetic libraries and have provided the basis for several effective new drugs [1]
Climacostol (5-[(2Z)-non-2-en-1-yl]benzene-1,3-diol) is a resorcinolic lipid physiologically produced by the freshwater ciliated protozoan Climacostomum virens for chemical defence against unicellular and multicellular predators [2]
We started from the same starting material as the climacostol synthesis
Summary
Natural products possess enormous structural and chemical diversity that is unsurpassed by any synthetic libraries and have provided the basis for several effective new drugs [1]. A great deal of effort is still aimed at discovering novel small molecules or trying to understand the structure–activity relationships of lead compounds This may help to find new derivatives exhibiting the optimum in potency/selectivity, and to exploit new therapeutic indications. Climacostol (5-[(2Z)-non-2-en-1-yl]benzene-1,3-diol) is a resorcinolic lipid physiologically produced by the freshwater ciliated protozoan Climacostomum virens for chemical defence against unicellular and multicellular predators [2]. It was structurally characterized and synthetized by Masaki et al [3], and has more recently been obtained as a pure compound in the natural and most bioactive
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