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

Structure-Based Design of a Lead Compound Derived from Natural Schweinfurthins with Antitumor Properties That Target Oxysterol-Binding Protein

Schweinfurthins (SWs) are naturally occurring prenylated stilbenes with promising anticancer properties. They act through a novel mechanism of action similar to that of other families of natural compounds. Their known target, oxysterol-binding protein (OSBP), plays a crucial role in controlling the intracellular distribution of cholesterol. We synthesized 15 analogues of SWs and demonstrated for the first time that their cytotoxicity as well as that of natural derivatives correlates with their affinity for OSBP. Through this extensive SAR study, we selected one synthetic analogue obtained in one step from SW-G. Using its fluorescence properties, we showed that this compound recapitulates the effect of natural SW-G in cells and confirmed that it leads to cell death via the same mechanism. Finally, after pilot PK experiments, we provided the first evidence of its in vivo efficacy in combination with temozolomide in a patient-derived glioblastoma xenograft model

Structure-Based Design of a Lead Compound Derived from Natural Schweinfurthins with Antitumor Properties That Target Oxysterol-Binding Protein

Schweinfurthins (SWs) are naturally occurring prenylated stilbenes with promising anticancer properties. They act through a novel mechanism of action similar to that of other families of natural compounds. Their known target, oxysterol-binding protein (OSBP), plays a crucial role in controlling the intracellular distribution of cholesterol. We synthesized 15 analogues of SWs and demonstrated for the first time that their cytotoxicity as well as that of natural derivatives correlates with their affinity for OSBP. Through this extensive SAR study, we selected one synthetic analogue obtained in one step from SW-G. Using its fluorescence properties, we showed that this compound recapitulates the effect of natural SW-G in cells and confirmed that it leads to cell death via the same mechanism. Finally, after pilot PK experiments, we provided the first evidence of its in vivo efficacy in combination with temozolomide in a patient-derived glioblastoma xenograft model