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1.
Molecules ; 24(20)2019 Oct 22.
Article in English | MEDLINE | ID: mdl-31652666

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).


Subject(s)
Trichodermin/analogs & derivatives , Animals , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/metabolism , Anti-Bacterial Agents/pharmacology , Antifungal Agents/chemical synthesis , Antifungal Agents/metabolism , Antifungal Agents/pharmacology , Candida albicans/drug effects , Cell Line , Female , Hepatocytes/drug effects , Humans , MCF-7 Cells , Mycotoxins/pharmacology , Rabbits , Trichoderma/enzymology , Trichoderma/genetics , Trichoderma/metabolism , Trichodermin/chemical synthesis , Trichodermin/chemistry , Trichodermin/pharmacology
2.
J Asian Nat Prod Res ; 17(1): 47-55, 2015.
Article in English | MEDLINE | ID: mdl-25290081

ABSTRACT

In an attempt to discover more potential antifungal agents, in this study, 21 novel trichodermin derivatives containing conjugated oxime ester (5a-5u) were designed and synthesized and were screened for in vitro antifungal activity. The bioassay tests showed that some of them exhibited good inhibitory activity against the tested pathogenic fungi. Compound 5a exhibited better activity against Pyricularia oryzae and Sclerotonia sclerotiorum than trichodermin, and compound 5j showed particular activity against P.oryzae and Botrytis cinerea. The quantitative structure-activity relationship (QSAR) indicated that log P and hardness were two critical parameters for the biological activities. The result suggested that these would be potential lead compounds for the development of fungicides with further structure modification.


Subject(s)
Antifungal Agents/chemical synthesis , Antifungal Agents/pharmacology , Fungicides, Industrial/chemical synthesis , Fungicides, Industrial/pharmacology , Oximes/chemical synthesis , Oximes/pharmacology , Trichodermin/chemical synthesis , Trichodermin/pharmacology , Antifungal Agents/chemistry , Botrytis/drug effects , Fungicides, Industrial/chemistry , Microbial Sensitivity Tests , Molecular Structure , Oximes/chemistry , Quantitative Structure-Activity Relationship , Trichodermin/chemistry
3.
Bioorg Med Chem Lett ; 24(15): 3565-8, 2014 Aug 01.
Article in English | MEDLINE | ID: mdl-24908609

ABSTRACT

To discover more potential antifungal agents, 17 novel trichodermin derivatives were designed and synthesized by modification of 3 and 4a. The structures of all the synthesized compounds were confirmed by (1)H NMR, ESI-MS and HRMS. Their antifungal activities against Ustilaginoidea oryzae and Pyricularia oryzae were evaluated. Most of the target compounds showed potent inhibitory activity, in which 4g showed superior inhibitory effects than 4a and commercial fungicide prochloraz. Furthermore, 4h demonstrated comparable inhibitory activity to 4a. Moreover, 4i and 4l exhibited excellent inhibitory activity for Pyricularia oryzae. Additionally, compound 9 was found to be more active against all tested fungal strains than 3, with EC50 values of 0.47 and 3.71 mg L(-1), respectively.


Subject(s)
Antifungal Agents/pharmacology , Magnaporthe/drug effects , Trichodermin/pharmacology , Ustilaginales/drug effects , Antifungal Agents/chemical synthesis , Antifungal Agents/chemistry , Dose-Response Relationship, Drug , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Structure-Activity Relationship , Trichodermin/chemical synthesis , Trichodermin/chemistry
4.
Chem Biodivers ; 10(4): 600-11, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23576346

ABSTRACT

Twenty new trichodermin derivatives, 2a-5, containing alkoxy, acyloxy, and Br groups in 4-, 8-, 9-, 10- and 16-positions were synthesized and characterized. The antifungal activities of the new compounds against rice false smut (Ustilaginoidea virens), rice sheath blight (Rhizoctonia solani), and rice blast (Magnaporthe grisea) were evaluated. The results of bioassays indicated that the antifungal activities were particularly susceptible to changes at 4-, 8-, and 16-positions, but low to changes at 9- and 10-positions. Most of these target compounds exhibited good antifungal activities at the concentration of 50 mg l(-1) . Compound 4 (9-formyltrichodermin; EC50 0.80 mg l(-1) ) with an CHO group at 9-position displayed nearly the same level of antifungal activity against Ustilaginoidea virens as the commercial fungicide prochloraz (EC50 0.82 mg l(-1) ), while compound 3f ((8R)-8-{[(E)-3-phenylprop-2-enoyl]oxy}trichodermin; EC50 3.58 and 0.74 mg l(-1) ) with a cinnamyloxy group at C(8) exhibited much higher antifungal activities against Rhizoctonia solani and Magnaporthe grisea than the commercial fungicides prochloraz (EC50 0.96 mg l(-1) ) and propiconazole (EC50 5.92 mg l(-1) ), respectively. These data reveal that compounds 3f and 4 possess high antifungal activities and may serve as lead compounds for the development of fungicides in the future.


Subject(s)
Antifungal Agents/chemical synthesis , Trichodermin/chemistry , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Hypocreales/drug effects , Magnaporthe/drug effects , Oryza/microbiology , Plant Diseases/microbiology , Rhizoctonia/drug effects , Structure-Activity Relationship , Triazoles/pharmacology , Trichodermin/chemical synthesis , Trichodermin/pharmacology
5.
Biochemistry ; 24(21): 5787-92, 1985 Oct 08.
Article in English | MEDLINE | ID: mdl-3936536

ABSTRACT

Trichodermin, a eukaryotic-specific antibiotic, inhibits protein synthesis in Drosophila cells. We have synthesized a 14C-labeled bromoacetyl derivative of trichodermin that binds to Drosophila 80S ribosomes and once bound reacts covalently with ribosomal proteins. It does not react with rRNA. Three large-subunit proteins (L1, L3, and L24) and three small-subunit proteins (S3/S5, 2/3S, and S8) are labeled by [14C] (bromoacetyl)trichodermin. Reaction with each of these proteins can be competed by an excess of unmodified trichodermin, indicating that the labeling has occurred from the native binding site of the parent drug. One of the (bromoacetyl)trichodermin-labeled proteins (S8) is also labeled by photoactivated puromycin in the A site. A second protein (S3/S5) is found to be labeled by a P-site affinity reagent. The results suggest that the trichodermin binding site spans both the small and large subunits and portions of both the A and P sites. These data combined with previous studies on the A and P sites of Drosophila ribosomes have allowed us to construct a model of the protein locations in this important active site.


Subject(s)
Affinity Labels/metabolism , Drosophila melanogaster/metabolism , Ribosomes/metabolism , Sesquiterpenes/metabolism , Trichodermin/metabolism , Animals , Binding Sites , Kinetics , Peptidyl Transferases/metabolism , Protein Binding , Protein Biosynthesis/drug effects , Ribosomes/drug effects , Trichodermin/analogs & derivatives , Trichodermin/chemical synthesis , Trichodermin/pharmacology
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