Asymmetric Total Synthesis of Euphordraculoate A and Pedrolide.

Here we report the asymmetric total syntheses of two rearranged tigliane diterpenoids, euphordraculoate A and pedrolide. A reductive dihydroxylation cascade and Nazarov cyclization were performed to generate euphordraculoate A, which was subjected to a cascade of Eu-promoted dienyl enolization, intramolecular Diels-Alder reaction and enol-ketone tautomerization to afford pedrolide, a pathway consistent with our proposal for the biogenesis of pedrolide.

New abietane and tigliane diterpenoids from the roots of Euphorbia fischeriana and their cytotoxic activities.

Three new abietane and two new tigliane diterpenoids were isolated from the roots Euphorbia fischeriana. Their structures were elucidated by spectroscopic methods and quantum chemical calculation. Compounds 4 and 5 exhibited the inhibitory activities against human cancer cells HeLa and HepG2, with IC50 ranging from 3.54 to 11.45 µM.

[Research progress in tigliane-type macrocyclic diterpenoids].

Tigliane type macrocyclic diterpenoids with special structures and diverse bioactivities are mainly extracted from plants of Euphorbiaceae and Thymelaeaceae. According to the different functional groups, they can be classified into types of phorbol esters, C-4 deoxyphorbol esters, C-12 deoxyphorbol esters, C-16 or C-17 substituted phorbol esters and others. Most of them present promising antiviral activities and cytotoxic activities and are expected to be developed as candidates for anti-AIDS, anti-tuberculosis, and anti-tumor clinical trials, demonstrating great potential for the application in healthcare. This paper reviews 115 novel tigliane-type diterpenoids discovered since 2013 and summarize their chemical structures and bioactivities, aiming to lay a foundation for further development and utilization of these compounds and provide new ideas for the development of clinical drugs.

Tigliane and rhamnofolane glycosides from Euphorbia wallichii prevent oxidative stress-induced neuronal death in PC-12 cells.

Tigliane and rhamnofolane diterpenoids bearing glycosyl substituents are rarely found in nature. In the current study, seven new tigliane glycosides, euphorwallsides A - G (1-7), and five new rhamnofolane glycosides, euphorwallsides H - L (8-12), were isolated from the whole plants of Euphorbia wallichii. Their structures were elucidated by a combination of spectroscopic, computational, and chemical means. The aglycones of 1-5 represent a rare class of 13-deoxygenated tiglianes, while those of 8-12 represent the first examples of 4-deoxygenated rhamnofolanes. 2, 3, 5, 7, 8, and 12 showed significant neuroprotective effects on sodium nitroprusside (SNP)-induced neuronal death in pheochromocytoma cell line PC-12 at 10 µM, being more active than the clinical drug, edaravone. Mechanistic study revealed that the most active compound, 3, could inhibit reactive oxygen species (ROS) accumulation and restore the mitochondrial membrane potential via modulating the Nrf2 signaling pathway in PC-12 cells.

New phorbol ester derivatives as potent anti-HIV agents.

Tigliane esters show many biological activities, including anti-HIV-1 activity. Our aim in this study was to establish structure-anti-HIV activity relationships for four series of tigliane-type diterpenoids. We synthesized and evaluated 29 new phorbol ester derivatives for anti-HIV activity and for cytotoxicity against human tumor cell lines. Among them, three derivatives, two phorbol-13-monoesters (5d and 5e) and a phorbol-12,13-diester (6a), showed significant anti-HIV activity. We found that better anti-HIV activity was often associated with a shorter acyl ester at C-13. Particularly, compounds with a phenyl ring in the ester side chain exhibited excellent anti-HIV activity and had good safety indexes. Due to its significant anti-HIV potency with a high selectivity index, phorbol-12,13-dicinnamoate (6a) was chosen as the potential candidate for further preclinical trials.

Macrocyclic Diterpenoids from Euphorbiaceae as A Source of Potent and Selective Inhibitors of Chikungunya Virus Replication.

Macrocyclic diterpenoids produced by plants of the Euphorbiaceae family are of considerable interest due to their high structural diversity; and their therapeutically relevant biological properties. Over the last decade many studies have reported the ability of macrocyclic diterpenoids to inhibit in cellulo the cytopathic effect induced by the chikungunya virus. This review; which covers the years 2011 to 2019; lists all macrocyclic diterpenoids that have been evaluated for their ability to inhibit viral replication. The structure-activity relationships and the probable involvement of protein kinase C in their mechanism of action are also detailed.

Gold Catalysis-Facilitated Rapid Synthesis of the Daphnane/Tigliane Tricyclic Core.

A concise approach to synthesize the 5-7-6 tricyclic carbon skeleton of the daphnane/tigliane diterpene natural products has been accomplished via a sequential gold-catalyzed furan formation and furan-allene [4+3] cycloaddition. This work provides new avenues for rapid and diverted synthesis of the medicinally important daphnane/tigliane diterpenes and their unnatural analogues.

Studies on the regio- and diastereo-selective epoxidation of daphnanes and tiglianes.

Daphnanes and tiglianes are diterpenes with a shared tricyclic 5-7-6 ring system. Many members exhibit significant biological activities often associated with protein kinase C signaling. Many of these natural products (~100) have a C6-C7 α-epoxide whose influence on biological activity is little studied. Using the more readily available phorbol ester PDBu as a test substrate, we report an efficient, and potentially general, α-epoxidation method based on a vanadium-catalyzed asymmetric epoxidation with bishydroxamic acid (BHA) ligands.

Tigliane and daphnane diterpenoids from Thymelaeaceae family: chemistry, biological activity, and potential in drug discovery.

Tigliane and daphnane diterpenoids are characteristically distributed in plants of the Thymelaeaceae family as well as the Euphorbiaceae family and are structurally diverse due to the presence of polyoxygenated functionalities in the polycyclic skeleton. These diterpenoids are known as toxic components, while they have been shown to exhibit a wide variety of biological activities, such as anti-cancer, anti-HIV, and analgesic activity, and are attracting attention in the field of natural product drug discovery. This review focuses on naturally occurring tigliane and daphnane diterpenoids from plants of the Thymelaeaceae family and provides an overview of their chemical structure, distribution, isolation, structure determination, chemical synthesis, and biological activities, with a prime focus on the recent findings.

Tigliane-and daphnane-type diterpenoids from the buds of Daphne genkwa with their cytotoxic activities.

Two new tigliane- and daphnane-type diterpenoids, given the trivial names daphnegens A-B (1-2) were isolated from the buds of Daphne genkwa. Their structures were assigned on the basis of extensive spectroscopic. The absolute configurations of both compounds were determined by comparison of their calculated and experimental CD curves. In addition, compounds 1-2 were tested for their cytotoxic activities against MCF-7 and HepG-2 human cancer cell lines, and compound 2 showed remarkable cytotoxic activity against HepG-2 cell line with the IC50 value of 11.5 µM.

Esterification with a Long-Chain Fatty Acid Elevates the Exposure Toxicity of Tigliane Diterpenoids from Euphorbia fischeriana Roots against Nematodes.

In this study, two tigliane diterpenoids, 12-deoxyphorbol-13-hexadecanoate and 12-deoxyphorbol-13-acetate (prostratin), were identified from the methanol extract of the roots of Euphorbia fischeriana and were found to have the ability to significantly reduce the survival of Caenorhabditis elegans. It was determined that exposure to these two compounds had toxic effects on the growth, reproduction, locomotion behavior, and accumulation of lipids and lipofuscin of the nematodes. Moreover, the transcription levels of the genes associated with lipid accumulation, apoptosis, insulin, and nuclear hormone synthesis in C. elegans were significantly influenced. Interestingly, 12-deoxyphorbol-13-hexadecanoate produced exposure toxicity at lower concentrations than that of prostratin. Pearson correlation analysis indicates that the elevated exposure toxicity of 12-deoxyphorbol-13-hexadecanoate may be the result of differing transcription levels, which result from the differential expression of fat-6, egl-38, and cep-1. These results reveal that esterification with a long-chain fatty acid elevates the exposure toxicity of this tigliane diterpenoid, thus providing a basis for the application of tigliane diterpenoids in plant-derived nematicides.

Cytotoxic tigliane diterpenoids from Euphorbia neorubella.

Two new tigliane diterpenes, named eupneonoids A (1) and B (2), together with four known analogues (3-6) were isolated from the whole plant of Euphorbia neorubella Bruyns. Their structures were deduced based on the detailed spectroscopic analysis. All the isolates displayed cytotoxic effects against A549 human tumor cell lines with IC50 values ranging from 1.318 to 7.042 µM.

A new tigliane-type diterpenoid from Euphorbia tirucalli.

Five tigliane (1-5) and one ingenane (6) diterpenoids were isolated from the ethanol extract of Euphorbia tirucalli. The structures of these compounds were identified based on analysis of their spectroscopic data. Among them, compound 12-O-(2E,4E,6E,8E-tetradecatetraenoyl)-13-O-isobutyroyl-4ß-deoxyphorbol (1) was a new tigliane. The Rho123 effluxion assay showed that tiglianes with a trans-fused 5/7 ring system such as compounds 1, 2, and 4 had potent inhibitory activity against P-glycoprotein in HepG2/ADR cells.

Potential HIV latency-reversing agents with STAT1-activating activity from the leaves of Wikstroemia chamaedaphne.

Developing highly effective HIV latency-reversing agent is an inportmant approach for the treatment of AIDS via the "shock and kill" of latent HIV. In this study, two unreported modified daphnane-type diterpenes (chamaedaphnelide A and epi-chamaedaphnelide A) and one unreported tigliane-type diterpene (chamaedaphnelide B), along with four known daphnane-type diterpenes and one known tigliane-type diterpene were obtained from the leaves of Wikstroemia chamaedaphne. Chamaedaphnelide A and epi-chamaedaphnelide A represents the first A ring cleavage daphnane-type backbone. Chamaedaphnelide A, epi-chamaedaphnelide A, chamaedaphnelide B, and 6α,7α-epoxy-5ß-hydroxy-12-deoxyphorbol-13-decanoate showed HIV latency-reversing activity, especially chamaedaphnelide B and 6α,7α-epoxy-5ß-hydroxy-12-deoxyphorbol-13-decanoate displayed equally potential to positive drugs prostratin with reversing latent HIV on more than 100-fold compared to unstimulated cells. Furthermore, the activation of STAT1 was involved in the HIV latency-reversing activity of these diterpenes, firstly demonstrating that daphnane- and tigliane-type diterpenes can rapidly activate STAT1 activity. Indeed, these results also supported that activating STAT1 activity is a pathway for reversing latent HIV.

Targeted isolation of diterpenoids and sesquiterpenoids from Daphne gemmata E. Pritz. ex Diels using molecular networking together with network annotation propagation and MS2LDA.

Investigation of the whole plant of Daphne gemmata E. Pritz. ex Diels (Thymelaeaceae) using molecular networking coupled to Network Annotation Propagation (NAP) and unsupervised substructure annotation (MS2LDA) led to the discovery of five tigliane diterpenoids, 14 guaiane sesquiterpenoids, one rhamnofolane diterpenoid and three carotene sesquiterpenoids. The structures of the eight undescribed compounds, daphnorbol A and daphnegemmatoids A-G, were characterized by detailed spectroscopic analyses, NMR and ECD calculations, application of Snatzke's method and single-crystal X-ray diffraction analysis. All isolated compounds were evaluated for their cytotoxic activities against HepG2, A549, and MCF-7 cells by MTT assay. Daphnorbol A exhibited significant cytotoxic activity against HepG2 and A549 cells with IC50 values of 4.06 µM and 6.35 µM, respectively. Prostratin showed potent cytotoxic activity against HepG2 and A549 cells with IC50 values of 6.06 µM and 5.45 µM, respectively. Further Hoechst 33,258 and AO-EB staining assays indicated that daphnorbol A and prostratin could induce apoptosis in HepG2 and A549 cells.

Bioactive tigliane diterpenoids from the latex of Euphorbia fischeriana.

Latex is a type of sticky endogenous fluids derived from diverse plants including Euphorbia fischeriana, and is of great scientific and commercial values. In the current study, it was demonstrated that the latex extracted from E. fischeriana strongly respelled the growth of cotton bollworm, Helicoverpa armigera. Using spectroscopic methods, HPLC, and GC-MS analyses, six aliphatic tigliane diterpenoids were isolated from the latex of E. fischeriana, among which three compounds (2, 3, and 5) were new. Two major compounds (1 and 4) exhibited remarkable antifeedant activity against H. armigera, with EC50 values at 2.59 and 15.32 µg/cm2, respectively. In addition, the quantification analysis of diterpenoids in different organs indicated that 4 was the most abundant constituent and was highly accumulated in the latex. Collectively, the current study highlighted that the diterpenoids in latex of E. fischeriana had a considerable antifeedant function against H. armigera, which might be employed for the future development of natural insecticides for organic farming.

Anti-HIV tigliane diterpenoids from Reutealis trisperma.

Bioassay-guided fractionation of the n-butanol extract from the branches and leaves of Reutealis trisperma resulted in the isolation of six undescribed (crotignoids L ~ Q) together with two known (12-deoxyphorbol-13-hexadecanoate and 12-deoxyphorbol-13-myristate) tigliane diterpenoids. Their structures, especially the absolute configurations, were determined from extensive spectroscopic studies, including 2D NMR spectra, CD data analysis and electronic circular dichroism (ECD) calculations. All isolates were tested for anti-HIV activity against HL4-3 virus in MT4 cells. Except for crotignoid Q, the remaining seven tigliane diterpenoids exhibited potent anti-HIV activity with IC50 values ranging from 0.0023 to 4.03 µM.

Research progress in tigliane-type macrocyclic diterpenoids / 中国中药杂志

Tigliane type macrocyclic diterpenoids with special structures and diverse bioactivities are mainly extracted from plants of Euphorbiaceae and Thymelaeaceae. According to the different functional groups, they can be classified into types of phorbol esters, C-4 deoxyphorbol esters, C-12 deoxyphorbol esters, C-16 or C-17 substituted phorbol esters and others. Most of them present promising antiviral activities and cytotoxic activities and are expected to be developed as candidates for anti-AIDS, anti-tuberculosis, and anti-tumor clinical trials, demonstrating great potential for the application in healthcare. This paper reviews 115 novel tigliane-type diterpenoids discovered since 2013 and summarize their chemical structures and bioactivities, aiming to lay a foundation for further development and utilization of these compounds and provide new ideas for the development of clinical drugs.

Diterpenes from buds of Wikstroemia chamaedaphne showing anti-hepatitis B virus activities.

Phytochemical study of the buds of Wikstroemia chamaedaphne Meisn. led to the isolation of seven previously undescribed diterpenes, including one tigliane diterpene (wikstchalide A), two daphnane diterpenes (wikstroelides W-X), and four lathyrane diterpenes (laurifoliosides A-B and 2-epi-laurifoliosides A-B), along with four known diterpenes. The structures of these compounds were established by extensive spectroscopic evidence and electronic circular dichroism (ECD) calculations. Wikstchalide A possesses a 5,6-epoxy ring in the tigliane skeleton. Two compounds exhibited potential anti-hepatitis B virus activities, with IC50 values of 46.5 and 88.3 µg/mL against hepatitis B virus (HBV) surface antigen (HBsAg), and six compounds showed certain inhibitory effects on HBV-DNA replication with the inhibition ratios ranging from 2.0% to 33.0% at the concentrations ranging from 0.39 to 6.25 µg/mL.

A new tigliane-type diterpene from Euphorbia dracunculoides Lam.

One new tigliane-type diterpene, 4-deoxy-4(ß)H-8-hydroperoxyphorbol-12-benzoate-13-isobutyrate (1), together with two known diterpenoids, 3-acetyl-5,8-dibenzoyl-14α-propanoyl-13,17-epoxy-7-myrsinaone diterpene with C9-C10 cyclised to form an additional lactone ring (2), Euphodendriane A (3) have been isolated from the whole plants of Euphorbia dracunculoides Lam. Their structures were elucidated by means of extensive spectroscopic analysis (NMR and HR-ESI-MS) and comparison with data reported in the literature. This is the first isolation of 8-hydroperoxy tigliane diterpene (1) from the genus of Euphorbia. All compounds were evaluated for their antifungal activities.