Trigocherrin A, the First Natural Chlorinated Daphnane Diterpene Orthoester from <i>Trigonostemon cherrieri</i>

Trigocherrin A, a chlorinated and highly oxygenated daphnane diterpenoid orthoester (DDO), was isolated from the bark of <i>Trigonostemon cherrieri</i>. Trigocherrin A is the first example of a naturally occurring halogenated DDO. Its structure was elucidated by comprehensive analysis of NMR spectroscopic data, and its absolute configuration was determined by comparison of experimental and theoretically calculated ECD spectra. Trigocherrin A exhibited a potent and selective effect against Chikungunya virus in Vero cells

Prostratin and 12‑<i>O</i>‑Tetradecanoylphorbol 13-Acetate Are Potent and Selective Inhibitors of Chikungunya Virus Replication

A chemical study of the Vietnamese plant species <i>Trigonostemon howii</i> led to the isolation of a new tigliane-type diterpenoid, trigowiin A (<b>1</b>), along with several known coumarins and phenylpropanoids. The planar structure and the relative configuration of compound <b>1</b> were elucidated based on spectroscopic analysis, including 1D- and 2D-NMR experiments, mass spectrometry, and comparison with literature data. Trigowiin A (<b>1</b>) exhibited moderate antiviral activity in a virus-cell-based assay for Chikungunya virus (CHIKV). Since the structure of compound <b>1</b> is closely related to those of well-known tigliane diterpenoids such as prostratin (<b>2</b>), phorbol (<b>3</b>), 12-<i>O</i>-tetradecanoylphorbol 13-acetate (TPA) (<b>4</b>), and 4α-TPA (<b>5</b>), the antiviral activity of the latter compounds was also evaluated against CHIKV, as well as in virus-cell-based assays of two additional members of the genus <i>Alphavirus</i> (Sindbis virus, SINV, and Semliki forest virus, SFV). Whereas prostratin inhibited CHIKV replication with a moderate EC₅₀ of 2.6 μM and a selectivity index (SI) approximating 30, compound <b>4</b> proved to be an extremely potent inhibitor, with an EC₅₀ of ∼3 nM and a SI near 2000. Interestingly, no or very little activity was observed on the replication of SINV and SFV

Trigocherrin A, the First Natural Chlorinated Daphnane Diterpene Orthoester from <i>Trigonostemon cherrieri</i>

Trigocherrin A, a chlorinated and highly oxygenated daphnane diterpenoid orthoester (DDO), was isolated from the bark of <i>Trigonostemon cherrieri</i>. Trigocherrin A is the first example of a naturally occurring halogenated DDO. Its structure was elucidated by comprehensive analysis of NMR spectroscopic data, and its absolute configuration was determined by comparison of experimental and theoretically calculated ECD spectra. Trigocherrin A exhibited a potent and selective effect against Chikungunya virus in Vero cells

Identification of a Series of Compounds with Potent Antiviral Activity for the Treatment of Enterovirus Infections

Rhinovirus (genus enterovirus) infections are responsible for many of the severe exacerbations of asthma and chronic obstructive pulmonary disease. Other members of the genus can cause life-threatening acute neurological infections. There is currently no antiviral drug approved for the treatment of such infections. We have identified a series of potent, broad-spectrum antiviral compounds that inhibit the replication of the human rhinovirus, Coxsackie virus, poliovirus, and enterovirus-71. The mechanism of action of the compounds has been established as inhibition of a lipid kinase, PI4KIIIβ. Inhibition of hepatitis C replication in a replicon assay correlated with enterovirus inhibition

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

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

Isolation of Premyrsinane, Myrsinane, and Tigliane Diterpenoids from <i>Euphorbia pithyusa</i> Using a Chikungunya Virus Cell-Based Assay and Analogue Annotation by Molecular Networking

Six new premyrsinol esters (<b>1</b>–<b>6</b>) and one new myrsinol ester (<b>8</b>) were isolated from an aerial parts extract of <i>Euphorbia pithyusa</i>, together with a known premyrsinol (<b>7</b>) and two known dideoxyphorbol esters (<b>9</b> and <b>10</b>), following a bioactivity-guided purification procedure using a chikungunya virus (CHIKV) cell-based assay. The structures of the new diterpene esters (<b>1</b>–<b>6</b> and <b>8</b>) were elucidated by MS and NMR spectroscopic data interpretation. Compounds <b>1</b>–<b>10</b> were evaluated against CHIKV replication, and results showed that the 4β-dideoxyphorbol ester <b>10</b> was the most active compound, with an EC₅₀ value of 4.0 ± 0.3 μM and a selectivity index of 10.6. To gain more insight into the structural diversity of diterpenoids produced by <i>E. pithyusa</i>, the initial extract and chromatographic fractions were analyzed by LC-MS/MS. The generated data were annotated using a molecular networking procedure and revealed that dozens of unknown premyrsinane, myrsinane, and tigliane analogues were present

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