Condensation of Macrocyclic Polyketides Produced by <i>Penicillium</i> sp. DRF2 with Mercaptopyruvate Represents a New Fungal Detoxification Pathway

Application of a refined procedure of experimental design and chemometric analysis to improve the production of curvularin-related polyketides by a marine-derived <i>Penicillium</i> sp. DRF2 resulted in the isolation and identification of cyclothiocurvularins <b>6</b>–<b>8</b> and cyclosulfoxicurvularins <b>10</b> and <b>11</b>, novel curvularins condensed with a mercaptolactate residue. Two additional new curvularins, <b>3</b> and <b>4</b>, are also reported. The structures of the sulfur-bearing curvularins were unambiguously established by analysis of spectroscopic data and by X-ray diffraction analysis. Analysis of stable isotope feeding experiments with [U–¹³C₃¹⁵N]-l-cysteine confirmed the presence of the 2-hydroxy-3-mercaptopropanoic acid residue in <b>6</b>–<b>8</b> and the oxidized sulfoxide in <b>10</b> and <b>11</b>. Cyclothiocurvularins A (<b>6</b>) and B (<b>7</b>) are formed by spontaneous reaction between 10,11-dehydrocurvularin (<b>2</b>) and mercaptopyruvate (<b>12</b>) obtained by transamination of cysteine. High ratios of [U–¹³C₃¹⁵N]-l-cysteine incorporation into cyclothiocurvularin B (<b>7</b>), the isolation of two diastereomers of cyclothiocurvularins, the lack of cytotoxicity of cyclothiocurvularin B (<b>7</b>) and its methyl ester (<b>8</b>), and the spontaneous formation of cyclothiocurvularins from 10,11-dehydrocurvularin and mercaptopyruvate provide evidence that the formation of cyclothiocurvularins may well correspond to a 10,11-dehydrocurvularin detoxification process by <i>Penicillium</i> sp. DRF2

Condensation of Macrocyclic Polyketides Produced by <i>Penicillium</i> sp. DRF2 with Mercaptopyruvate Represents a New Fungal Detoxification Pathway

Application of a refined procedure of experimental design and chemometric analysis to improve the production of curvularin-related polyketides by a marine-derived <i>Penicillium</i> sp. DRF2 resulted in the isolation and identification of cyclothiocurvularins <b>6</b>–<b>8</b> and cyclosulfoxicurvularins <b>10</b> and <b>11</b>, novel curvularins condensed with a mercaptolactate residue. Two additional new curvularins, <b>3</b> and <b>4</b>, are also reported. The structures of the sulfur-bearing curvularins were unambiguously established by analysis of spectroscopic data and by X-ray diffraction analysis. Analysis of stable isotope feeding experiments with [U–¹³C₃¹⁵N]-l-cysteine confirmed the presence of the 2-hydroxy-3-mercaptopropanoic acid residue in <b>6</b>–<b>8</b> and the oxidized sulfoxide in <b>10</b> and <b>11</b>. Cyclothiocurvularins A (<b>6</b>) and B (<b>7</b>) are formed by spontaneous reaction between 10,11-dehydrocurvularin (<b>2</b>) and mercaptopyruvate (<b>12</b>) obtained by transamination of cysteine. High ratios of [U–¹³C₃¹⁵N]-l-cysteine incorporation into cyclothiocurvularin B (<b>7</b>), the isolation of two diastereomers of cyclothiocurvularins, the lack of cytotoxicity of cyclothiocurvularin B (<b>7</b>) and its methyl ester (<b>8</b>), and the spontaneous formation of cyclothiocurvularins from 10,11-dehydrocurvularin and mercaptopyruvate provide evidence that the formation of cyclothiocurvularins may well correspond to a 10,11-dehydrocurvularin detoxification process by <i>Penicillium</i> sp. DRF2

Condensation of Macrocyclic Polyketides Produced by <i>Penicillium</i> sp. DRF2 with Mercaptopyruvate Represents a New Fungal Detoxification Pathway

Application of a refined procedure of experimental design and chemometric analysis to improve the production of curvularin-related polyketides by a marine-derived <i>Penicillium</i> sp. DRF2 resulted in the isolation and identification of cyclothiocurvularins <b>6</b>–<b>8</b> and cyclosulfoxicurvularins <b>10</b> and <b>11</b>, novel curvularins condensed with a mercaptolactate residue. Two additional new curvularins, <b>3</b> and <b>4</b>, are also reported. The structures of the sulfur-bearing curvularins were unambiguously established by analysis of spectroscopic data and by X-ray diffraction analysis. Analysis of stable isotope feeding experiments with [U–¹³C₃¹⁵N]-l-cysteine confirmed the presence of the 2-hydroxy-3-mercaptopropanoic acid residue in <b>6</b>–<b>8</b> and the oxidized sulfoxide in <b>10</b> and <b>11</b>. Cyclothiocurvularins A (<b>6</b>) and B (<b>7</b>) are formed by spontaneous reaction between 10,11-dehydrocurvularin (<b>2</b>) and mercaptopyruvate (<b>12</b>) obtained by transamination of cysteine. High ratios of [U–¹³C₃¹⁵N]-l-cysteine incorporation into cyclothiocurvularin B (<b>7</b>), the isolation of two diastereomers of cyclothiocurvularins, the lack of cytotoxicity of cyclothiocurvularin B (<b>7</b>) and its methyl ester (<b>8</b>), and the spontaneous formation of cyclothiocurvularins from 10,11-dehydrocurvularin and mercaptopyruvate provide evidence that the formation of cyclothiocurvularins may well correspond to a 10,11-dehydrocurvularin detoxification process by <i>Penicillium</i> sp. DRF2

Condensation of Macrocyclic Polyketides Produced by <i>Penicillium</i> sp. DRF2 with Mercaptopyruvate Represents a New Fungal Detoxification Pathway

Application of a refined procedure of experimental design and chemometric analysis to improve the production of curvularin-related polyketides by a marine-derived <i>Penicillium</i> sp. DRF2 resulted in the isolation and identification of cyclothiocurvularins <b>6</b>–<b>8</b> and cyclosulfoxicurvularins <b>10</b> and <b>11</b>, novel curvularins condensed with a mercaptolactate residue. Two additional new curvularins, <b>3</b> and <b>4</b>, are also reported. The structures of the sulfur-bearing curvularins were unambiguously established by analysis of spectroscopic data and by X-ray diffraction analysis. Analysis of stable isotope feeding experiments with [U–¹³C₃¹⁵N]-l-cysteine confirmed the presence of the 2-hydroxy-3-mercaptopropanoic acid residue in <b>6</b>–<b>8</b> and the oxidized sulfoxide in <b>10</b> and <b>11</b>. Cyclothiocurvularins A (<b>6</b>) and B (<b>7</b>) are formed by spontaneous reaction between 10,11-dehydrocurvularin (<b>2</b>) and mercaptopyruvate (<b>12</b>) obtained by transamination of cysteine. High ratios of [U–¹³C₃¹⁵N]-l-cysteine incorporation into cyclothiocurvularin B (<b>7</b>), the isolation of two diastereomers of cyclothiocurvularins, the lack of cytotoxicity of cyclothiocurvularin B (<b>7</b>) and its methyl ester (<b>8</b>), and the spontaneous formation of cyclothiocurvularins from 10,11-dehydrocurvularin and mercaptopyruvate provide evidence that the formation of cyclothiocurvularins may well correspond to a 10,11-dehydrocurvularin detoxification process by <i>Penicillium</i> sp. DRF2