Abstract
Trichothecene mycotoxins are recognized as highly bioactive compounds that can be used in the design of new useful bioactive molecules. In Trichoderma brevicompactum, the first specific step in trichothecene biosynthesis is carried out by a terpene cyclase, trichodiene synthase, that catalyzes the conversion of farnesyl diphosphate to trichodiene and is encoded by the tri5 gene. Overexpression of tri5 resulted in increased levels of trichodermin, a trichothecene-type toxin, which is a valuable tool in preparing new molecules with a trichothecene skeleton. In this work, we developed the hemisynthesis of trichodermin and trichodermol derivatives in order to evaluate their antimicrobial and cytotoxic activities and to study the chemo-modulation of their bioactivity. Some derivatives with a short chain at the C-4 position displayed selective antimicrobial activity against Candida albicans and they showed MIC values similar to those displayed by trichodermin. It is important to highlight the cytotoxic selectivity observed for compounds 9, 13, and 15, which presented average IC50 values of 2 μg/mL and were cytotoxic against tumorigenic cell line MCF-7 (breast carcinoma) and not against Fa2N4 (non-tumoral immortalized human hepatocytes).
Highlights
Natural products (NPs, secondary metabolites) are an invaluable source of inspiration in drug design and development
The potency and broad biological activity shown by trichodermin (1) sparked our interest in amassing adequate amounts of this molecule to complete a study of its biological activity and to perform chemical transformations on the 1 skeleton with a view to modulating or enhancing this biological activity
We have worked on obtaining transformants of T. brevicompactum in order to study the functionality of the genes involved in the biosynthesis of trichothecenes and to obtain mutants to efficiently produce large quantities of trichodermin (1) or trichodermol (2), the final precursor of 1 in its biosynthetic pathway
Summary
Natural products (NPs, secondary metabolites) are an invaluable source of inspiration in drug design and development. Of all new drugs approved between 1981 and 2014 (n = 1562), 50% are natural products, are derived from natural products, or are synthetic molecules inspired by or that mimic natural products [3]. Molecules 2019, 24, 3811 pathway [4]. All terpenes are derived from the repetitive fusion of branched five-carbon units based on an isopentene skeleton, and most of the chemical intermediates in their biosynthetic pathway are known [5]. Typical structures contain carbon skeletons represented by (C5)n and are classified as hemiterpenes (C5), monoterpenes (C10), sesquiterpenes (C15), diterpenes (C20), sesterterpenes (C25), triterpenes (C30), and tetraterpenes (C40) [6]
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