Structurally Diverse Diterpenoids from Sandwithia guyanensis

Bioassay-guided fractionation of an EtOAc extract of the trunk bark of Sandwithia guyanensis, using a chikungunya virus (CHIKV)-cell-based assay, afforded 17 new diterpenoids <b>1</b>–<b>17</b> and the known jatrointelones A and C (<b>18</b> and <b>19</b>). The new compounds included two tetranorditerpenoids <b>1</b> and <b>2</b>, a trinorditerpenoid <b>3</b>, euphoractines P-W (<b>4</b>–<b>11</b>), and euphactine G (<b>13</b>) possessing the rare 5/6/7/3 (<b>4</b>–<b>7</b>), 5/6/6/4 (<b>8</b>–<b>11</b>), and 5/6/8 (<b>13</b>) fused ring skeletons, sikkimenoid E (<b>12</b>), and jatrointelones J-M (<b>14</b>–<b>17</b>) possessing jatropholane and lathyrane carbon skeletons, respectively. Jatrointelones J (<b>14</b>) and M (<b>17</b>) represent the first naturally occurring examples of C-15 nonoxidized lathyrane-type diterpenoids. The structures of the new compounds were elucidated by NMR spectroscopic data analysis. The relative configuration of compound <b>16</b> and the absolute configurations of compounds <b>3</b>–<b>6</b> and <b>14</b> were determined by single-crystal X-ray diffraction analysis. In addition, jatrointelone K (<b>15</b>) was chemically transformed to euphoractine T (<b>8</b>) supporting the biosynthetic relationships between the two types of diterpenoids. Only compound <b>15</b> showed a moderate anti-CHIKV activity with an EC₅₀ value of 14 μM. Finally, using a molecular networking-based dereplication strategy, several close analogues of 12-<i>O</i>-tetradecanoylphorbol-13-acetate (TPA), one of the most potent inhibitors of CHIKV replication, were dereplicated

Structurally Diverse Diterpenoids from Sandwithia guyanensis

Bioassay-guided fractionation of an EtOAc extract of the trunk bark of Sandwithia guyanensis, using a chikungunya virus (CHIKV)-cell-based assay, afforded 17 new diterpenoids <b>1</b>–<b>17</b> and the known jatrointelones A and C (<b>18</b> and <b>19</b>). The new compounds included two tetranorditerpenoids <b>1</b> and <b>2</b>, a trinorditerpenoid <b>3</b>, euphoractines P-W (<b>4</b>–<b>11</b>), and euphactine G (<b>13</b>) possessing the rare 5/6/7/3 (<b>4</b>–<b>7</b>), 5/6/6/4 (<b>8</b>–<b>11</b>), and 5/6/8 (<b>13</b>) fused ring skeletons, sikkimenoid E (<b>12</b>), and jatrointelones J-M (<b>14</b>–<b>17</b>) possessing jatropholane and lathyrane carbon skeletons, respectively. Jatrointelones J (<b>14</b>) and M (<b>17</b>) represent the first naturally occurring examples of C-15 nonoxidized lathyrane-type diterpenoids. The structures of the new compounds were elucidated by NMR spectroscopic data analysis. The relative configuration of compound <b>16</b> and the absolute configurations of compounds <b>3</b>–<b>6</b> and <b>14</b> were determined by single-crystal X-ray diffraction analysis. In addition, jatrointelone K (<b>15</b>) was chemically transformed to euphoractine T (<b>8</b>) supporting the biosynthetic relationships between the two types of diterpenoids. Only compound <b>15</b> showed a moderate anti-CHIKV activity with an EC₅₀ value of 14 μM. Finally, using a molecular networking-based dereplication strategy, several close analogues of 12-<i>O</i>-tetradecanoylphorbol-13-acetate (TPA), one of the most potent inhibitors of CHIKV replication, were dereplicated

Structurally Diverse Diterpenoids from Sandwithia guyanensis

Bioassay-guided fractionation of an EtOAc extract of the trunk bark of Sandwithia guyanensis, using a chikungunya virus (CHIKV)-cell-based assay, afforded 17 new diterpenoids <b>1</b>–<b>17</b> and the known jatrointelones A and C (<b>18</b> and <b>19</b>). The new compounds included two tetranorditerpenoids <b>1</b> and <b>2</b>, a trinorditerpenoid <b>3</b>, euphoractines P-W (<b>4</b>–<b>11</b>), and euphactine G (<b>13</b>) possessing the rare 5/6/7/3 (<b>4</b>–<b>7</b>), 5/6/6/4 (<b>8</b>–<b>11</b>), and 5/6/8 (<b>13</b>) fused ring skeletons, sikkimenoid E (<b>12</b>), and jatrointelones J-M (<b>14</b>–<b>17</b>) possessing jatropholane and lathyrane carbon skeletons, respectively. Jatrointelones J (<b>14</b>) and M (<b>17</b>) represent the first naturally occurring examples of C-15 nonoxidized lathyrane-type diterpenoids. The structures of the new compounds were elucidated by NMR spectroscopic data analysis. The relative configuration of compound <b>16</b> and the absolute configurations of compounds <b>3</b>–<b>6</b> and <b>14</b> were determined by single-crystal X-ray diffraction analysis. In addition, jatrointelone K (<b>15</b>) was chemically transformed to euphoractine T (<b>8</b>) supporting the biosynthetic relationships between the two types of diterpenoids. Only compound <b>15</b> showed a moderate anti-CHIKV activity with an EC₅₀ value of 14 μM. Finally, using a molecular networking-based dereplication strategy, several close analogues of 12-<i>O</i>-tetradecanoylphorbol-13-acetate (TPA), one of the most potent inhibitors of CHIKV replication, were dereplicated

Structurally Diverse Diterpenoids from Sandwithia guyanensis

Bioassay-guided fractionation of an EtOAc extract of the trunk bark of Sandwithia guyanensis, using a chikungunya virus (CHIKV)-cell-based assay, afforded 17 new diterpenoids <b>1</b>–<b>17</b> and the known jatrointelones A and C (<b>18</b> and <b>19</b>). The new compounds included two tetranorditerpenoids <b>1</b> and <b>2</b>, a trinorditerpenoid <b>3</b>, euphoractines P-W (<b>4</b>–<b>11</b>), and euphactine G (<b>13</b>) possessing the rare 5/6/7/3 (<b>4</b>–<b>7</b>), 5/6/6/4 (<b>8</b>–<b>11</b>), and 5/6/8 (<b>13</b>) fused ring skeletons, sikkimenoid E (<b>12</b>), and jatrointelones J-M (<b>14</b>–<b>17</b>) possessing jatropholane and lathyrane carbon skeletons, respectively. Jatrointelones J (<b>14</b>) and M (<b>17</b>) represent the first naturally occurring examples of C-15 nonoxidized lathyrane-type diterpenoids. The structures of the new compounds were elucidated by NMR spectroscopic data analysis. The relative configuration of compound <b>16</b> and the absolute configurations of compounds <b>3</b>–<b>6</b> and <b>14</b> were determined by single-crystal X-ray diffraction analysis. In addition, jatrointelone K (<b>15</b>) was chemically transformed to euphoractine T (<b>8</b>) supporting the biosynthetic relationships between the two types of diterpenoids. Only compound <b>15</b> showed a moderate anti-CHIKV activity with an EC₅₀ value of 14 μM. Finally, using a molecular networking-based dereplication strategy, several close analogues of 12-<i>O</i>-tetradecanoylphorbol-13-acetate (TPA), one of the most potent inhibitors of CHIKV replication, were dereplicated

Structurally Diverse Diterpenoids from Sandwithia guyanensis

Bioassay-guided fractionation of an EtOAc extract of the trunk bark of Sandwithia guyanensis, using a chikungunya virus (CHIKV)-cell-based assay, afforded 17 new diterpenoids <b>1</b>–<b>17</b> and the known jatrointelones A and C (<b>18</b> and <b>19</b>). The new compounds included two tetranorditerpenoids <b>1</b> and <b>2</b>, a trinorditerpenoid <b>3</b>, euphoractines P-W (<b>4</b>–<b>11</b>), and euphactine G (<b>13</b>) possessing the rare 5/6/7/3 (<b>4</b>–<b>7</b>), 5/6/6/4 (<b>8</b>–<b>11</b>), and 5/6/8 (<b>13</b>) fused ring skeletons, sikkimenoid E (<b>12</b>), and jatrointelones J-M (<b>14</b>–<b>17</b>) possessing jatropholane and lathyrane carbon skeletons, respectively. Jatrointelones J (<b>14</b>) and M (<b>17</b>) represent the first naturally occurring examples of C-15 nonoxidized lathyrane-type diterpenoids. The structures of the new compounds were elucidated by NMR spectroscopic data analysis. The relative configuration of compound <b>16</b> and the absolute configurations of compounds <b>3</b>–<b>6</b> and <b>14</b> were determined by single-crystal X-ray diffraction analysis. In addition, jatrointelone K (<b>15</b>) was chemically transformed to euphoractine T (<b>8</b>) supporting the biosynthetic relationships between the two types of diterpenoids. Only compound <b>15</b> showed a moderate anti-CHIKV activity with an EC₅₀ value of 14 μM. Finally, using a molecular networking-based dereplication strategy, several close analogues of 12-<i>O</i>-tetradecanoylphorbol-13-acetate (TPA), one of the most potent inhibitors of CHIKV replication, were dereplicated

Structurally Diverse Diterpenoids from Sandwithia guyanensis

Bioassay-guided fractionation of an EtOAc extract of the trunk bark of Sandwithia guyanensis, using a chikungunya virus (CHIKV)-cell-based assay, afforded 17 new diterpenoids <b>1</b>–<b>17</b> and the known jatrointelones A and C (<b>18</b> and <b>19</b>). The new compounds included two tetranorditerpenoids <b>1</b> and <b>2</b>, a trinorditerpenoid <b>3</b>, euphoractines P-W (<b>4</b>–<b>11</b>), and euphactine G (<b>13</b>) possessing the rare 5/6/7/3 (<b>4</b>–<b>7</b>), 5/6/6/4 (<b>8</b>–<b>11</b>), and 5/6/8 (<b>13</b>) fused ring skeletons, sikkimenoid E (<b>12</b>), and jatrointelones J-M (<b>14</b>–<b>17</b>) possessing jatropholane and lathyrane carbon skeletons, respectively. Jatrointelones J (<b>14</b>) and M (<b>17</b>) represent the first naturally occurring examples of C-15 nonoxidized lathyrane-type diterpenoids. The structures of the new compounds were elucidated by NMR spectroscopic data analysis. The relative configuration of compound <b>16</b> and the absolute configurations of compounds <b>3</b>–<b>6</b> and <b>14</b> were determined by single-crystal X-ray diffraction analysis. In addition, jatrointelone K (<b>15</b>) was chemically transformed to euphoractine T (<b>8</b>) supporting the biosynthetic relationships between the two types of diterpenoids. Only compound <b>15</b> showed a moderate anti-CHIKV activity with an EC₅₀ value of 14 μM. Finally, using a molecular networking-based dereplication strategy, several close analogues of 12-<i>O</i>-tetradecanoylphorbol-13-acetate (TPA), one of the most potent inhibitors of CHIKV replication, were dereplicated

Structurally Diverse Diterpenoids from Sandwithia guyanensis

Bioassay-guided fractionation of an EtOAc extract of the trunk bark of Sandwithia guyanensis, using a chikungunya virus (CHIKV)-cell-based assay, afforded 17 new diterpenoids <b>1</b>–<b>17</b> and the known jatrointelones A and C (<b>18</b> and <b>19</b>). The new compounds included two tetranorditerpenoids <b>1</b> and <b>2</b>, a trinorditerpenoid <b>3</b>, euphoractines P-W (<b>4</b>–<b>11</b>), and euphactine G (<b>13</b>) possessing the rare 5/6/7/3 (<b>4</b>–<b>7</b>), 5/6/6/4 (<b>8</b>–<b>11</b>), and 5/6/8 (<b>13</b>) fused ring skeletons, sikkimenoid E (<b>12</b>), and jatrointelones J-M (<b>14</b>–<b>17</b>) possessing jatropholane and lathyrane carbon skeletons, respectively. Jatrointelones J (<b>14</b>) and M (<b>17</b>) represent the first naturally occurring examples of C-15 nonoxidized lathyrane-type diterpenoids. The structures of the new compounds were elucidated by NMR spectroscopic data analysis. The relative configuration of compound <b>16</b> and the absolute configurations of compounds <b>3</b>–<b>6</b> and <b>14</b> were determined by single-crystal X-ray diffraction analysis. In addition, jatrointelone K (<b>15</b>) was chemically transformed to euphoractine T (<b>8</b>) supporting the biosynthetic relationships between the two types of diterpenoids. Only compound <b>15</b> showed a moderate anti-CHIKV activity with an EC₅₀ value of 14 μM. Finally, using a molecular networking-based dereplication strategy, several close analogues of 12-<i>O</i>-tetradecanoylphorbol-13-acetate (TPA), one of the most potent inhibitors of CHIKV replication, were dereplicated

Antiviral Activity of Flexibilane and Tigliane Diterpenoids from <i>Stillingia lineata</i>

In an effort to identify new potent and selective inhibitors of chikungunya virus and HIV-1 and HIV-2 virus replication, the endemic Mascarene species <i>Stillingia lineata</i> was investigated. LC/MS and bioassay-guided purification of the EtOAc leaf extract using a chikungunya virus-cell-based assay led to the isolation of six new (<b>4</b>–<b>9</b>) and three known (<b>1</b>–<b>3</b>) tonantzitlolones possessing the rare C₂₀-flexibilane skeleton, along with tonantzitloic acid (<b>10</b>), a new linear diterpenoid, and three new (<b>11</b>, <b>13</b>, and <b>15</b>) and two known (<b>12</b> and <b>14</b>) tigliane-type diterpenoids. The planar structures of the new compounds and their relative configurations were determined by spectroscopic analysis, and their absolute configurations were determined through comparison with literature data and from biogenetic considerations. These compounds were investigated for selective antiviral activity against chikungunya virus (CHIKV), Semliki Forest virus, Sindbis virus, and, for compounds <b>11</b>–<b>15</b>, the HIV-1 and HIV-2 viruses. Compounds <b>12</b>–<b>15</b> were found to be the most potent and are selective inhibitors of CHIKV, HIV-1, and HIV-2 replication. In particular, compound <b>14</b> inhibited CHIKV replication with an EC₅₀ value of 1.2 μM on CHIKV and a selectivity index of >240, while compound <b>15</b> inhibited HIV-1 and HIV-2 with EC₅₀ values of 0.043 and 0.018 μM, respectively. It was demonstrated further that potency and selectivity are sensitive to the substitution pattern on the tigliane skeleton. The cytotoxic activities of compounds <b>1</b>–<b>10</b> were evaluated against the HCT-116, MCF-7, and PC3 cancer cell lines

Natural Inhibitors of the RhoA–p115 Complex from the Bark of <i>Meiogyne baillonii</i>

In an effort to find potent natural inhibitors of RhoA and p115 signaling G-proteins, a systematic in vitro evaluation using enzymatic and plasmonic resonance assays was undertaken on 11 317 plant extracts. The screening procedure led to the selection of the New Caledonian endemic species <i>Meiogyne baillonii</i> for a chemical investigation. Using a bioguided isolation procedure, three enediyne-γ-butyrolactones (<b>1</b>–<b>3</b>) and two enediyne-γ-butenolides (<b>4</b> and <b>5</b>), named sapranthins H–L, respectively, two enediyne carboxylic acid (<b>6</b> and <b>7</b>), two depsidones, stictic acid (<b>8</b>) and baillonic acid (<b>9</b>), aristolactams AIa and AIIa (<b>10</b> and <b>11</b>), and two aporphines, dehydroroemerine (<b>12</b>) and noraristolodione (<b>13</b>), were isolated from the ethyl acetate extract of the bark. The structures of the new compounds (<b>1</b>–<b>6</b>, <b>9</b>, and <b>11</b>) and their relative configurations were established by NMR spectroscopic analysis and by X-ray diffraction analysis for compound <b>9</b>. Only stictic acid (<b>8</b>) exhibited a significant inhibiting activity of the RhoA–p115 complex, with an EC₅₀ value of 0.19 ± 0.05 mM. This is the first time that a natural inhibitor of the complex RhoA–p115’s activity was discovered from an HTS performed over a collection of higher plant extracts. Thus, stictic acid (<b>8</b>) could be used as the first reference compound inhibiting the interaction between RhoA and p115

Natural Inhibitors of the RhoA–p115 Complex from the Bark of <i>Meiogyne baillonii</i>

In an effort to find potent natural inhibitors of RhoA and p115 signaling G-proteins, a systematic in vitro evaluation using enzymatic and plasmonic resonance assays was undertaken on 11 317 plant extracts. The screening procedure led to the selection of the New Caledonian endemic species <i>Meiogyne baillonii</i> for a chemical investigation. Using a bioguided isolation procedure, three enediyne-γ-butyrolactones (<b>1</b>–<b>3</b>) and two enediyne-γ-butenolides (<b>4</b> and <b>5</b>), named sapranthins H–L, respectively, two enediyne carboxylic acid (<b>6</b> and <b>7</b>), two depsidones, stictic acid (<b>8</b>) and baillonic acid (<b>9</b>), aristolactams AIa and AIIa (<b>10</b> and <b>11</b>), and two aporphines, dehydroroemerine (<b>12</b>) and noraristolodione (<b>13</b>), were isolated from the ethyl acetate extract of the bark. The structures of the new compounds (<b>1</b>–<b>6</b>, <b>9</b>, and <b>11</b>) and their relative configurations were established by NMR spectroscopic analysis and by X-ray diffraction analysis for compound <b>9</b>. Only stictic acid (<b>8</b>) exhibited a significant inhibiting activity of the RhoA–p115 complex, with an EC₅₀ value of 0.19 ± 0.05 mM. This is the first time that a natural inhibitor of the complex RhoA–p115’s activity was discovered from an HTS performed over a collection of higher plant extracts. Thus, stictic acid (<b>8</b>) could be used as the first reference compound inhibiting the interaction between RhoA and p115