Oxidation of Isodrimeninol with PCC Yields Drimane Derivatives with Activity against <i>Candida</i> Yeast by Inhibition of Lanosterol 14-Alpha Demethylase
<i>Candida</i> species cause an opportunistic yeast infection called Candidiasis, which is responsible for more than 50,000 deaths every year around the world. Effective treatments against candidiasis caused by non-albicans <i>Candida</i> species such as <i>C. glabrata,...
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| Format: | Article |
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MDPI AG
2020-07-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/10/8/1101 |
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| author | Victor Marin Andres Iturra Andres Opazo Bernd Schmidt Matthias Heydenreich Leandro Ortiz Verónica A. Jiménez Cristian Paz |
| author_facet | Victor Marin Andres Iturra Andres Opazo Bernd Schmidt Matthias Heydenreich Leandro Ortiz Verónica A. Jiménez Cristian Paz |
| author_sort | Victor Marin |
| collection | DOAJ |
| description | <i>Candida</i> species cause an opportunistic yeast infection called Candidiasis, which is responsible for more than 50,000 deaths every year around the world. Effective treatments against candidiasis caused by non-albicans <i>Candida</i> species such as <i>C. glabrata, C. parapsilosis, C. aureus,</i> and <i>C.</i> <i>krusei</i> are limited due to severe resistance to conventional antifungal drugs. Natural drimane sesquiterpenoids have shown promising antifungal properties against <i>Candida</i> yeast and have emerged as valuable candidates for developing new candidiasis therapies. In this work, we isolated isodrimeninol (<b>C1</b>) from barks of <i>Drimys winteri</i> and used it as starting material for the hemi-synthesis of four sesquiterpenoids by oxidation with pyridinium chlorochromate (PCC). The structure of the products (<b>C2</b>, <b>C3</b>, <b>C4,</b> and <b>C5</b>) was elucidated by 1D and 2D NMR spectroscopy resulting in <b>C4</b> being a novel compound. Antifungal activity assays against <i>C. albicans, C. glabrata,</i> and <i>C. krusei</i> revealed that <b>C4</b> exhibited an increased activity (IC<sub>50</sub> of 75 μg/mL) compared to <b>C1</b> (IC<sub>50</sub> of 125 μg/mL) in all yeast strains. The antifungal activity of <b>C1</b> and <b>C4</b> was rationalized in terms of their capability to inhibit lanosterol 14-alpha demethylase using molecular docking, molecular dynamics simulations, and MM/GBSA binding free energy calculations. In silico analysis revealed that <b>C1</b> and <b>C4</b> bind to the outermost region of the catalytic site of 14-alpha demethylase and block the entrance of lanosterol (<b>LAN</b>) to the catalytic pocket. Binding free energy estimates suggested that <b>C4</b> forms a more stable complex with the enzyme than <b>C1</b>, in agreement with the experimental evidence. Based on this new approach it is possible to design new drimane-type sesquiterpenoids for the control of <i>Candida</i> species as inhibitors of 14-alpha demethylase. |
| first_indexed | 2024-03-10T18:14:18Z |
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| institution | Directory Open Access Journal |
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| last_indexed | 2024-03-10T18:14:18Z |
| publishDate | 2020-07-01 |
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| spelling | doaj.art-b0051dd1542b44d19f234fce1b2972a82023-11-20T07:50:36ZengMDPI AGBiomolecules2218-273X2020-07-01108110110.3390/biom10081101Oxidation of Isodrimeninol with PCC Yields Drimane Derivatives with Activity against <i>Candida</i> Yeast by Inhibition of Lanosterol 14-Alpha DemethylaseVictor Marin0Andres Iturra1Andres Opazo2Bernd Schmidt3Matthias Heydenreich4Leandro Ortiz5Verónica A. Jiménez6Cristian Paz7Laboratory of Natural Products & Drug Discovery, Department of Basic Science, Universidad de La Frontera, Av. Francisco Salazar 01145, 4780000 Temuco, ChileLaboratory of Natural Products & Drug Discovery, Department of Basic Science, Universidad de La Frontera, Av. Francisco Salazar 01145, 4780000 Temuco, ChileUniversidad de Concepción, Departamento de Microbiología, Laboratorio de Investigación en Agentes Antibacterianos (LIAA), Barrio Universitario S/N, 160-C 1807 Concepción, ChileUniversität Potsdam, Institut für Chemie, Karl-Liebknecht-Str. 24-25, D-14476 Potsdam, GermanyUniversität Potsdam, Institut für Chemie, Karl-Liebknecht-Str. 24-25, D-14476 Potsdam, GermanyUniversidad Austral de Chile, Instituto de Ciencias Química, Facultad de Ciencias, Universidad Austral de Chile, Casilla 567, 5091000 Valdivia, ChileUniversidad Andres Bello, Sede Concepción, Departamento de Ciencias Químicas, Facultad de Ciencias Exactas, Autopista Concepción-Talcahuano 7100, 4030000 Talcahuano, ChileLaboratory of Natural Products & Drug Discovery, Department of Basic Science, Universidad de La Frontera, Av. Francisco Salazar 01145, 4780000 Temuco, Chile<i>Candida</i> species cause an opportunistic yeast infection called Candidiasis, which is responsible for more than 50,000 deaths every year around the world. Effective treatments against candidiasis caused by non-albicans <i>Candida</i> species such as <i>C. glabrata, C. parapsilosis, C. aureus,</i> and <i>C.</i> <i>krusei</i> are limited due to severe resistance to conventional antifungal drugs. Natural drimane sesquiterpenoids have shown promising antifungal properties against <i>Candida</i> yeast and have emerged as valuable candidates for developing new candidiasis therapies. In this work, we isolated isodrimeninol (<b>C1</b>) from barks of <i>Drimys winteri</i> and used it as starting material for the hemi-synthesis of four sesquiterpenoids by oxidation with pyridinium chlorochromate (PCC). The structure of the products (<b>C2</b>, <b>C3</b>, <b>C4,</b> and <b>C5</b>) was elucidated by 1D and 2D NMR spectroscopy resulting in <b>C4</b> being a novel compound. Antifungal activity assays against <i>C. albicans, C. glabrata,</i> and <i>C. krusei</i> revealed that <b>C4</b> exhibited an increased activity (IC<sub>50</sub> of 75 μg/mL) compared to <b>C1</b> (IC<sub>50</sub> of 125 μg/mL) in all yeast strains. The antifungal activity of <b>C1</b> and <b>C4</b> was rationalized in terms of their capability to inhibit lanosterol 14-alpha demethylase using molecular docking, molecular dynamics simulations, and MM/GBSA binding free energy calculations. In silico analysis revealed that <b>C1</b> and <b>C4</b> bind to the outermost region of the catalytic site of 14-alpha demethylase and block the entrance of lanosterol (<b>LAN</b>) to the catalytic pocket. Binding free energy estimates suggested that <b>C4</b> forms a more stable complex with the enzyme than <b>C1</b>, in agreement with the experimental evidence. Based on this new approach it is possible to design new drimane-type sesquiterpenoids for the control of <i>Candida</i> species as inhibitors of 14-alpha demethylase.https://www.mdpi.com/2218-273X/10/8/1101IsodrimeninolPCC oxidation<i>Candida</i> yeastmolecular dockinglanosterol 14-alpha demethylase |
| spellingShingle | Victor Marin Andres Iturra Andres Opazo Bernd Schmidt Matthias Heydenreich Leandro Ortiz Verónica A. Jiménez Cristian Paz Oxidation of Isodrimeninol with PCC Yields Drimane Derivatives with Activity against <i>Candida</i> Yeast by Inhibition of Lanosterol 14-Alpha Demethylase Biomolecules Isodrimeninol PCC oxidation <i>Candida</i> yeast molecular docking lanosterol 14-alpha demethylase |
| title | Oxidation of Isodrimeninol with PCC Yields Drimane Derivatives with Activity against <i>Candida</i> Yeast by Inhibition of Lanosterol 14-Alpha Demethylase |
| title_full | Oxidation of Isodrimeninol with PCC Yields Drimane Derivatives with Activity against <i>Candida</i> Yeast by Inhibition of Lanosterol 14-Alpha Demethylase |
| title_fullStr | Oxidation of Isodrimeninol with PCC Yields Drimane Derivatives with Activity against <i>Candida</i> Yeast by Inhibition of Lanosterol 14-Alpha Demethylase |
| title_full_unstemmed | Oxidation of Isodrimeninol with PCC Yields Drimane Derivatives with Activity against <i>Candida</i> Yeast by Inhibition of Lanosterol 14-Alpha Demethylase |
| title_short | Oxidation of Isodrimeninol with PCC Yields Drimane Derivatives with Activity against <i>Candida</i> Yeast by Inhibition of Lanosterol 14-Alpha Demethylase |
| title_sort | oxidation of isodrimeninol with pcc yields drimane derivatives with activity against i candida i yeast by inhibition of lanosterol 14 alpha demethylase |
| topic | Isodrimeninol PCC oxidation <i>Candida</i> yeast molecular docking lanosterol 14-alpha demethylase |
| url | https://www.mdpi.com/2218-273X/10/8/1101 |
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