Synthesis of Trichodermin Derivatives and Their Antimicrobial and Cytotoxic Activities

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).

New Trichothecenes Isolated from the Marine Algicolous Fungus Trichoderma brevicompactum

“…Compounds 5, 7, and 8 exerted attenuation of S1 protein-stimulated MMP-9-mediated gelatinolysis of 66.1 ± 3.1%, 63.4 ± 0.4%, and 92.1 ± 1.9% at 10 µM, respectively (Figure 3). Trichodermol ( 8) is a member of a family of fungal metabolites that show broad-spectrum antifungal activities and moderate cytotoxic activity against the MCF-7 line (breast carcinoma) [20,22]. Trichoderminol (compound 5) was first isolated in 2017 and has antifungal, antimicroalgal, and antiviral activities [4,17].…”

Sesquiterpenoids Specially Produced by Fungi: Structures, Biological Activities, Chemical and Biosynthesis (2015–2020)

“…The semisynthesis of several trichodermin and trichodermol derivatives has been developed (Scheme 15) [127]. 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.…”

“…Ochraceopone A 363 exhib-Scheme 15. Chemical transformations were carried out on trichodermin and trichodermol for the preparation of compounds 344-357 (Reference [127]).…”

Pipecolisporin, a Novel Cyclic Peptide with Antimalarial and Antitrypanosome Activities from a Wheat Endophytic Nigrospora oryzae

“…Although historically plants have been the main source of antiplasmodial natural products [ 8 ], many antimicrobial secondary metabolites from fungal endophytes have also been described as potential antiprotozoal agents. These include, among others, altenusin [ 9 ], xylariaquinone A [ 10 ], codinaeopsin [ 11 ], fusaripeptide A [ 12 ], strasseriolides A–D [ 13 ], leucinostatins [ 14 ], griseofulvin [ 15 ], or trichodermin [ 16 ]. Other interesting biological properties exhibited by endophytic metabolites include antifungal, anti-inflammatory, antiproliferative, or anticancer activities [ 17 ].…”