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

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

Synthesis, Biological Evaluation, and Molecular Modeling of Natural and Unnatural Flavonoidal Alkaloids, Inhibitors of Kinases

The screening of the ICSN chemical library on various disease-relevant protein kinases led to the identification of natural flavonoidal alkaloids of unknown configuration as potent inhibitors of the CDK1 and CDK5 kinases. We thus developed an efficient and modular synthetic strategy for their preparation and that of analogues in order to determine the absolute configuration of the active natural flavonoidal alkaloids and to provide further insights on the structure–activity relationships in this series. The structural determinants of the interaction between some flavonoidal alkaloids with specific kinases were also evaluated using molecular modeling

Goniomedines A and B: Unprecedented Bisindole Alkaloids Formed through Fusion of Two Indole Moieties via a Dihydropyran Unit

Two novel bisindole alkaloids, goniomedines A (<b>1</b>) and B (<b>2</b>), possessing an unprecedented quebrachamine–pleioarpamine-type skeleton, in which indole moieties are fused via a dihydropyran unit, were isolated from the stem bark of <i>Gonioma malagasy.</i> The structures were elucidated by comprehensive analysis of MS and NMR spectroscopic data. Their absolute configurations were deduced following the comparison of experimental and theoretically calculated ECD spectra and through biogenetic considerations. Goniomedine B (<b>2</b>) exhibited moderate activity against <i>Plasmodium falciparum</i>

One-Pot Synthesis of Vinca Alkaloids–Phomopsin Hybrids

Hybrids of vinca alkaloids and phomopsin A have been elaborated with the aim of interfering with the “vinca site” and the “peptide site” of the vinca domain in tubulin. They were synthesized by an efficient one-pot procedure that directly links the octahydrophomopsin lateral chain to the velbenamine moiety of 7′-<i>homo</i>-anhydrovinblastine. In their modeled complexes with tubulin, these hybrids were found to superimpose nicely on the tubulin-bound structures of vinblastine and phomopsin A. This good matching can account for the fact that two of them are very potent inhibitors of microtubules assembly and are cytotoxic against four cancer cell lines

Synthesis and Biological Evaluation of a New Series of Highly Functionalized 7′-<i>homo</i>-Anhydrovinblastine Derivatives

Sixteen new 7′-<i>homo</i>-anhydrovinblastine derivatives were prepared in one or two steps from vinorelbine by means of an original and regiospecific rearrangement and subsequent diastereoselective reduction. This strategy has allowed fast access to a family of vinca alkaloid derivatives with an enlarged and functionalized ring C′. Their synthesis and biological evaluation are reported. One compound (compound <b>35</b>) is 1.7 times more active than vinorelbine as a tubulin assembly inhibitor. Moreover, some of these compounds are highly cytotoxic, and two of them are more potent than vinorelbine on HCT116 and K562 cell lines. Molecular modeling studies, carried out with two of the new vinca derivatives, provide useful hints about how a given functionalization introduced at positions 7′ and 8′ of the C′ ring results in improved binding interactions between one of the new derivatives and the interdimer interface when compared to the parent compound vinblastine

Cytotoxic Lignans from Fruits of <i>Cleistanthus indochinensis</i>: Synthesis of Cleistantoxin Derivatives

Two new aryl-tetralin lignans, <b>1</b> and <b>2</b>, were isolated from the fruits of <i>Cleistanthus indochinensis</i> by bioassay-guided purification. Their structures were determined by spectroscopic analysis including MS and 2D NMR. The absolute configurations of <b>1</b> and <b>2</b> were established from examination of their CD spectra. Compound <b>1</b> was cytotoxic against KB cells with an IC₅₀ value of 0.022 μM, while compound <b>2</b> had weaker cytotoxicity, with an IC₅₀ value of 1.4 μM. When tested against other cancer cell lines (MCF-7, MCF-7R, and HT29), <b>1</b> showed an IC₅₀ of 0.014 against MCF-7R cells and an IC₅₀ of 0.036 μM against MCF-7 cells. A series of amide derivatives of a new lactone, homoderivatives of <b>1</b>, were prepared. Of these derivatives, only compound <b>3</b> had weak cytotoxicity against KB cells

Acetylcholinesterase Inhibitors from the Leaves of <i>Macaranga kurzii</i>

Bioassay-guided fractionation of an extract of leaves of <i>Macaranga kurzii</i> yielded four new compounds, a stilbene (furanokurzin, <b>1</b>) and three flavonoids (macakurzin A–C, <b>2</b>–<b>4</b>). Nine known compounds were also isolated (<b>5</b>–<b>13</b>). Their structures were determined by spectroscopic analyses including MS and 2D NMR. The isolates were all evaluated for acetylcholinesterase inhibitory activity. Compound <b>6</b> (<i>trans</i>-3,5-dimethoxystilbene) exhibited the greatest activity (IC₅₀ 9 μM). Cytotoxic evaluation against KB cells showed that compound <b>7</b> had an IC₅₀ of 4 μM, followed by <b>11</b> (IC₅₀ 10 μM) and <b>3</b> (IC₅₀ 13 μM)

Cytotoxic Lignans from Fruits of <i>Cleistanthus indochinensis</i>: Synthesis of Cleistantoxin Derivatives

Two new aryl-tetralin lignans, <b>1</b> and <b>2</b>, were isolated from the fruits of <i>Cleistanthus indochinensis</i> by bioassay-guided purification. Their structures were determined by spectroscopic analysis including MS and 2D NMR. The absolute configurations of <b>1</b> and <b>2</b> were established from examination of their CD spectra. Compound <b>1</b> was cytotoxic against KB cells with an IC₅₀ value of 0.022 μM, while compound <b>2</b> had weaker cytotoxicity, with an IC₅₀ value of 1.4 μM. When tested against other cancer cell lines (MCF-7, MCF-7R, and HT29), <b>1</b> showed an IC₅₀ of 0.014 against MCF-7R cells and an IC₅₀ of 0.036 μM against MCF-7 cells. A series of amide derivatives of a new lactone, homoderivatives of <b>1</b>, were prepared. Of these derivatives, only compound <b>3</b> had weak cytotoxicity against KB cells