Synthesis of Trichodermin Derivatives and Their Antimicrobial and Cytotoxic Activities
by
Javier E. Barúa 1,2, Mercedes de la Cruz 3
, Nuria de Pedro 3, Bastien Cautain 3, Rosa Hermosa 4, Rosa E. Cardoza 5, Santiago Gutiérrez 5, Enrique Monte 4, Francisca Vicente 3 and Isidro G. Collado 2,*
Javier E. Barúa 1,2, Mercedes de la Cruz 3, Nuria de Pedro 3, Bastien Cautain 3, Rosa Hermosa 4, Rosa E. Cardoza 5, Santiago Gutiérrez 5, Enrique Monte 4, Francisca Vicente 3 and Isidro G. Collado 2,*
1
Biological Chemistry Department, Chemistry Science Faculty, National University of Asunción, Ruta Mcal. Estigarribia Km 11.5, San Lorenzo 2160, Paraguay
2
Department of Organic Chemistry, Campus of Puerto Real, Science Faculty, University of Cádiz, 11510 Puerto Real, Cádiz, Spain
3
Fundación Medina, Avda. del Conocimiento 34, Armilla, 18016 Granada, Spain
4
Department of Microbiology and Genetics, Spanish-Portuguese Institute for Agricultural Research (CIALE), University of Salamanca, Campus of Villamayor, Rio Duero 12, 37185 Salamanca, Spain
5
University of León, Campus of Ponferrada, Superior and Technical Universitary School of Agricultural Engineers, Area of Microbiology, Avda. Astorga s/n, 24400 Ponferrada, Spain
*
Author to whom correspondence should be addressed.
Molecules 2019, 24(20), 3811; https://doi.org/10.3390/molecules24203811
Received: 1 October 2019 / Revised: 17 October 2019 / Accepted: 21 October 2019 / Published: 22 October 2019
(This article belongs to the Section Bioorganic Chemistry)
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).
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Keywords:
trichothecene; sesquiterpenes; tri genes; synthesis; antimicrobial; cytotoxic bioactivity
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MDPI and ACS Style
Barúa, J.E.; de la Cruz, M.; de Pedro, N.; Cautain, B.; Hermosa, R.; Cardoza, R.E.; Gutiérrez, S.; Monte, E.; Vicente, F.; Collado, I.G. Synthesis of Trichodermin Derivatives and Their Antimicrobial and Cytotoxic Activities. Molecules 2019, 24, 3811.
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