As part of efforts to identify natural modulators of multi-drug-resistant breast cancer, Euphorbia mauritanica L. chloroform extract yielded four undescribed oxygenated diterpenes, including three nor-ent-abietanes, euphomauritanol C-E (1-3), and one polyacylated jatrophane, euphomauritanolide A (4), along with two knowns, helioscopinolide A (5) and enukokurin (6). The chemical structures and configurations of compounds were established by combination of HRMS, FTIR, and NMR spectroscopic tools along with experimental and calculated TDDFT-ECD. The cytotoxicity evaluation of isolated compounds against the MCF-7ADR revealed 4 and 2 are the most potent with IC50 values of 3.2 ± 0.58 and 4.67 ± 0.29 μM, respectively. Co-administration of compounds 4 and 2 with DOX improved its cytotoxic effect, with a combination index value of 0.41 for 4, indicating a synergistic effect. Mechanistically, 4 modulated DOX anticancer properties via potentiating DOX-induced Go/G1 cell cycle arrest rather than G2M arrest of DOX alone and shifting the cell death of DOX to be mainly apoptotic cell death. Furthermore, 4 alone and combined with DOX showed promising anti-migratory effects against MCF-7ADR. In conclusion, 4 showed promising co-chemotherapeutic effects to the DOX against MCF-7ADR, indicating that this compound possesses potential as an auspicious lead chemical to target breast cancer cells resistant to doxorubicin.

Emerging evidence indicates the inhibition of neuroinflammation is an important and promising strategy for managing Alzheimer's disease. Anti-neuroinflammatory agents are potential drug leads. In this work, seventeen diterpenoids (1-17) including ten previously undescribed ones, named excoaglolides A-J (1-10) were isolated from the stems and twigs of the mangrove plant, Excoecaria agallocha L. The undescribed diterpenoids could be categorized into four subclasses, viz., ent-isopimaranes (1-4), ent-beyeranes (5-7), ent-atisanes (8-9), and ent-labdane (10). Their structures including absolute configurations were unambiguously characterized by spectroscopic methods, single crystal X-ray diffraction analyses, ECD calculations, and modified Mosher's method. Notably, compound 1 was a rare 3,4-seco-3,11-lactone-ent-isopimarane, whereas compound 2 was the first 2,3-seco-2,11-lactone-ent-isopimarane; compound 5 represents the first example of 2,3-seco-2-nor-1,3-lactone-ent-beyerane, compound 8 was the first member of 18(4 → 3)-abeo-ent-atisane forming through a Wagner-Meerwein rearrangement, compound 9 was an unusual rearranged 3,4-seco-ent-atisane possessing a cyclobutane ring, and compound 10 featuring a rare chlorine substitution at C-15. In addition, the stereochemistry of the known diterpenoid excoagallochaol D (11) with a unique 6/7/4-fused ring system was firstly determined by single crystal X-ray diffraction analyses in this study. Compounds 1, 12, 15, and 16 showed significant nitric oxide production inhibition in lipopolysaccharide-induced BV-2 microglial cells with IC50 values ranging from 2.0 to 13.5 μM. Further mechanistic investigations revealed that compound 1 inhibited macrophage polarization and decreased the expression levels of representative inflammation-related genes, including IL-1β, IL-6, TNF-α, COX-2, and iNOS. These were associated with suppressions of proteins related to inflammasome, including caspase 1 and NLRP3, and secretion of IL-1β. The present study revealed that the mangrove diterpenoid excoaglolide A (1) would be promising structure base for developing neuroinflammation-related neurodegeneration diseases.

Molecular networking (MN) analysis facilitates the targeted discovery of novel constituents and enhances the understanding of natural products. While various molecular networks could reduce the effects of redundant nodes, current research is still limited by the interference from the same and coeluted metabolites, including isotopic peaks, a variety of adduct ions, in-source fragmentations, and dehydration. This research proposes a novel strategy: stratified precursor lists (SPLs)-guided Metabolite-Based Molecular Networking (MBMN), which ensures a high-quality MS2 spectrum for each metabolite precursor due to the absence of retention time overlap with other coeluted metabolites, and each node represents a unique metabolite. By collecting over 40 MS2 databases from multiple online platforms and public databases, an integrated MS2 database (IM2DB) containing more than two million MS2 fragmentation data was constructed. In addition, a customized MS1 database (M1DB) of reported compounds was also created. Nodes representing known compounds were annotated compared to the IM2DB and M1DB. Combining with MBMN analysis significantly enhances compound identification and characterization, thereby facilitating the discerning of potential novel constituents. To demonstrate the applicability of this strategy, we selected Euphorbia helioscopia L. as an example. 135 nodes were annotated, and three reference nodes were obtained. From the selected 35 target nodes, 10 purified compounds were isolated and elucidated. Among these, three were identified as novel compounds, while the remaining nine were discovered for the first time in Euphorbia helioscopia L. By using this strategy, we can effectively minimize the interference from redundant nodes and discover potentially new compounds.

Phosphorylation of checkpoint kinase 1 at Ser-345 (p-CHK1(S345)) mediates the replication stress response in cancer cells, leading to chemotherapy resistance. Therefore, finding inhibitors of p-CHK1(S345) is currently a promising strategy to prevent acquired drug resistance. In this study, 14 ingenane diterpenoids (1-14), involving two undescribed compounds possessing an unprecedented exocyclic double bond Δ6(20), were identified from Euphorbia peplus. The inhibitory effects of the isolated compounds on p-CHK1(S345) and their structure-activity relationship (SAR) were investigated. Compounds 7 and 8 presented the strongest inhibitory effects, abrogated cell cycle arrest, and caused the accumulation of DNA damage, improving the sensitivity of cancer cells to chemotherapeutic drugs. An in vivo assay confirmed the enhancement of 8 on the anticancer effect of topotecan via blocking of p-CHK1(S345). Mechanistically, 8 increased CHK1 ubiquitination to inhibit p-CHK1(S345) via activation of protein kinase C (PKC). PKC activation was first found to enhance CHK1 ubiquitination to block p-CHK1(S345). Above all, this finding not only indicates that compound 8 could be developed as a novel CHK1 inhibitor but also reveals a previously unrecognized role of PKC in regulating cancer chemotherapy sensitivity.

Euphthymifolols A-E (1-5), five undescribed jatrophane diterpenoids feature with a typically 5/12 bicyclic skeleton, were characterised from the aerial parts of Euphorbia thymifolia L. A thorough analysis of the spectroscopic data and biosynthetic pathway elucidated their planar structures and stereoconfiguration. Compound 4 exhibited moderate nitric oxide (NO) inhibitory activity (IC50 63.3 ± 1.94 μM) against LPS-induced BV-2 microglia cells.

Cycloeuphoboetirane A (2), a new diterpene with an unprecedented pentacyclic skeleton, has been obtained from lathyrane euphoboetirane A (1). A formal intramolecular [2+2] cycloaddition reaction catalyzed by Sordaria tomento-alba ST1-UCA is involved, providing new evidence for the existence of enzymes capable of catalyzing this reaction. A biomimetic photochemical conversion was also achieved by benzophenone with light-emitting diode irradiation.

Eleven new ent-abietane diterpenoid lactones, designated euphjatrophanes H-R (1-11), were isolated from the whole plants of Euphorbia peplus, along with nine previously identified congeners (12-20). Their structures, including absolute configurations, were elucidated through a combination of NMR, HRESIMS, single-crystal X-ray diffraction, and calculations of ECD and DP4 + technologies. Notably, the absolute configurations of six compounds 1, 2, 4, 5, 6, and 7 were unambiguously determined by single-crystal X-ray diffraction analyses, conducted with Cu Kα radiation. The anti-inflammatory potential of all ent-abietane diterpenoid lactones was evaluated on macrophages. Compounds 6-9, 12-16 and 19 significantly suppressed nitric oxide production, while 10 μM of compounds 6, 9, 11 and 16 remarkably suppressed the mRNA expression of IL-6, IL-1β, and TNFα in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages. Notably, compound 6 demonstrated a dose-dependent inhibition of the levels of inflammatory mediators (IL-6, IL-1β, and TNFα). Furthermore, compound 6 effectively suppressed FOXO1 expression and reduced the phosphorylation level of NF-κB p65. These findings suggest that compound 6 might be a promising candidate for treating inflammation-related diseases.

The Euphorbia plants are famous for their diterpenoid constituents with diverse structures and broad biological activities. Herein, the discovery of 15 ingenane diterpenoids including 10 previously unreported ones (1-10) from Euphorbia antiquorum was presented. Structures of the undescribed compounds were established via detailed spectroscopic analyses. Meanwhile, a preliminary anti-inflammatory screening revealed that compound 6 showed significant inhibitory activity against the production of nitric oxide, as well as downregulated the expression of COX-2 and IL-6, in lipopolysaccharide-stimulated RAW264.7 macrophages. Further mechanistical exploration revealed that compound 6 could exert its anti-inflammatory effect by inhibiting NF-κB and activating Nrf2 signaling pathways.

Liver fibrosis is an urgent clinical problem without effective therapies. Here we conducted a high-content screening on a natural Euphorbiaceae diterpenoid library to identify a potent anti-liver fibrosis lead, 12-deoxyphorbol 13-palmitate (DP). Leveraging a photo-affinity labeling approach, apolipoprotein L2 (APOL2), an endoplasmic reticulum (ER)-rich protein, was identified as the direct target of DP. Mechanistically, APOL2 is induced in activated hepatic stellate cells upon transforming growth factor-β1 (TGF-β1) stimulation, which then binds to sarcoplasmic/ER calcium ATPase 2 (SERCA2) to trigger ER stress and elevate its downstream protein kinase R-like ER kinase (PERK)-hairy and enhancer of split 1 (HES1) axis, ultimately promoting liver fibrosis. As a result, targeting APOL2 by DP or ablation of APOL2 significantly impairs APOL2-SERCA2-PERK-HES1 signaling and mitigates fibrosis progression. Our findings not only define APOL2 as a novel therapeutic target for liver fibrosis but also highlight DP as a promising lead for treatment of this symptom.

Euphorbialoid A (1) belongs to the rare diterpenoid family of premyrsinanes and exhibits potent anti-inflammatory effects. The 5/7/6/3-membered carbocycle (ABCD-ring) of 1 contains 11 contiguous stereocenters and seven oxygen-containing functional groups. Moreover, four of the six hydroxy groups of 1 are concentrated in the southern sector and flanked by four structurally different acyl groups. The dense array of various functional groups with disparate reactivities on the tetracyclic ABCD-ring presents a daunting challenge for the chemical synthesis of 1. As a reflection of its formidable complexity, synthesis of 1 or any other premyrsinane diterpenoids has not yet been reported. Here, we devised a novel strategy comprising two stages and achieved the first total synthesis of 1 (35 steps as the longest linear sequence). In the first stage, the ABCD-ring was expeditiously assembled by integrating three powerful transformations: (1) Pt-doped TiO2-catalyzed radical coupling to attach a northern chain to a 6/3-membered CD-ring, (2) Pd-catalyzed decarboxylative asymmetric allylation to construct a quaternary carbon with a southern chain, and (3) a Co-mediated Pauson-Khand reaction to cyclize the two chains into the 5/7-membered AB-ring. In the second stage, three-dimensional structures of the ABCD-ring intermediates were utilized to stereoselectively fabricate the A-ring and site-selectively append the four different acyl groups. In the present total synthesis, we revealed the significance of orchestrating the multistep reaction sequence and incorporating cyclic protective groups. The overall strategy and tactics provide new insights into designing synthetic routes to premyrsinanes and densely oxygenated terpenoids decorated with diverse acyl groups.

One new lathyrane-type diterpenoid, euphlathin A (1), and 11 known analogues (2-12), were isolated from the fruits of Euphorbia lathyris. Their structures were elucidated by spectroscopic data. The absolute configurations of 1 were established by single-crystal X-ray crystallography. All diterpenoids (1-12) were evaluated for antiproliferative activity against the human hypertrophic scar (HTS) cells. Compound 1 exhibited significantly against HTS cells growth with an IC50 value of 6.33 μM. Morphological features of apoptosis were evaluated in 1-treated HTS cells. Wound healing assays indicated that 1 significantly inhibited the migration of HTS at 24 h and 48 h. Compound 1 effectively induced apoptosis of HTS, which was associated with G2/M or S phase cell cycle arrest. Flow cytometric analysis showed that the treatment by 1 significantly induced HTS cell apoptosis in a dose-dependent manner. Overall, euphlathin A (1) has the potential to be a therapeutic agent for the treatment of hyperplastic scar therapy.

Promoting endogenous neurogenesis for brain repair is emerging as a promising strategy to mitigate the functional impairments associated with various neurological disorders characterized by neuronal death. Diterpenes featuring tigliane, ingenane, jatrophane and lathyrane skeletons, frequently found in Euphorbia plant species, are known protein kinase C (PKC) activators and exhibit a wide variety of pharmacological properties, including the stimulation of neurogenesis. Microbial transformation of these diterpenes represents a green and sustainable methodology that offers a hitherto little explored approach to obtaining novel derivatives and exploring structure-activity relationships. In the present study, we report the biotransformation of euphoboetirane A (4) and epoxyboetirane A (5), two lathyrane diterpenoids isolated from Euphorbia boetica, by Mucor circinelloides MC NRRL3631. Our findings revealed the production of nine biotransformation products (6-14), including jatrophane derivatives originated through an unprecedented rearrangement from the parent lathyranes. The chemical structures and absolute configurations of the new compounds were elucidated through comprehensive analysis using NMR and ECD spectroscopy, as well as MS. The study evaluated how principal metabolites and their derivatives affect TGFα and NRG1 release, as well as their potential to promote proliferation or differentiation in cultures of NSC isolated from the SVZ of adult mice. In order to shed some light on the mechanisms underlying the ability of 12 as a neurogenic compound, the interactions of selected compounds with PKC δ-C1B were analyzed through molecular docking and molecular dynamics. Based on these, it clearly appears that the ability of compound 12 to form both acceptor and donor hydrogen bonds with certain amino acid residues in the enzyme pocket leads to a higher affinity compound-PKC complex, which correlates with the observed biological activity.

Fourteen undescribed diterpenoids, including eleven lathyrane diterpenoids wallathyanes A-K (1-11) and three ent-isopimarane diterpenoids wallisopiranes A-C (12-14), together with fourteen known analogues 15-28, were obtained from the whole plant of Euphorbia wallichii. Their chemical structures were elucidated by spectroscopic data analysis, experimental electronic circular dichroism measurements, and X-ray crystallography. Bioactivity screening indicated that compound 2 exhibited an inhibitory effect on NO generation in LPS-stimulated RAW264.7 macrophage cells with an IC50 value of 4.76 ± 1.08 μM. The network pharmacology and molecular docking studies also revealed that compound 2 can bind with the potential targets GRB, AKT1, MAPK1, MAPK14, HSP90AA1, PIK3R1, PIK3CB, PRKACA, SRC, CASP3, RXRA, PTPNA11, ZAP70, and PRKC of inflammation.

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.

Lathyrisone A (1), a diterpene with an undescribed tricyclic 6/6/6 fused carbon skeleton, along with spirolathyrisins B-D (3-5), three diterpenes with a rare [4.5.0] spirocyclic carbon skeleton, and one known compound (2) were isolated from the roots of Euphorbia lathyris. Their chemical structures were characterized by extensive spectroscopic analysis, X-ray crystallography, ECD and quantum chemistry calculation. A plausible biosynthetic pathway for compounds 1-5 was proposed, which suggested it is a competitive pathway for ingenol biosynthesis in the plant. The anti-fungal activities of these compounds were tested, especially, compound 2 showed stronger anti-fungal activities against Fusarium oxysporum and Alternaria alternata than the positive control fungicide thiophanate-methyl. The preliminary structure-activity relationship of compounds 1-5 was also discussed. These results not only expanded the chemical diversities of E. lathyris, but also provided a lead compound for the control of plant pathogens.

The present review article thoroughly analyses natural products and their derived phytoconstituents as a rich source of plausible anticancer drugs. The study thoroughly explores the chemical components derived from various natural sources, thus emphasizing their unique structural characteristics and therapeutic potential as an anticancer agent. The review contains the critical chemical constituents' in-depth molecular mechanisms, their source's chemical structures and the categories. The review also comprises an exhaustive and comprehensive analysis of different chemical spacing parameters of the anticancer agents derived from natural products. It compares them with USFDA-approved synthetic anticancer drugs up to 2020, thus providing a meaningful understanding of the relationship between natural and synthetic compounds portraying the anticancer assets. The review also delves more deeply into the chemical analysis of the heterocyclic moieties from the natural product arena, illustrating the anticancer mechanisms. The present article is, therefore, expected to serve as a valuable resource for natural product and medicinal chemists, encouraging and promoting an integrated approach to exploit the potential of natural products in drug discovery development and translational research, which have a prerequisite of bench to bedside approach. The work could guide researchers toward innovative approaches for the ever-evolving field of anticancer drug discovery.

The first systematic acylated diversification of naturally scarce premyrsinane diterpenes, together with their biosynthetic precursors lathyrane diterpene were carried out. Two new series of premyrsinane derivates (1a-32a) and lathyrane derivates (1-32) were synthesized from the naturally abundant lathyrane diterpene Euphorbia factor L3 through a bioinspired approach. The cholinesterase inhibitory and neuroprotective activities of these diterpenes were investigated to explore potential anti-Alzheimer's disease (AD) bioactive lead compounds. In general, the lathyrane diterpenes showed the better acetylcholinesterase (AChE) inhibitory activity than that of premyrsinanes. The lathyrane derivative 17 bearing a 3-dimethylaminobenzoyl moiety showed the best AChE inhibition effect with the IC50 value of 7.1 μM. Molecular docking demonstrated that 17 could bond with AChE well (-8 kal/mol). On the other hand, premyrsinanes showed a better neuroprotection profile against H2O2-induced injury in SH-SY5Y cells. Among them, the premyrsinane diterpene 16a had significant neuroprotective effect with the cell viability rate of 113.5 % at 12.5 μM (the model group with 51.2 %). The immunofluorescence, western blot and reactive oxygen species (ROS) analysis were conducted to demonstrate the mechanism of 16a. Furthermore, a preliminary SAR analysis of the two categories of diterpenes was performed to provide the insights for anti-AD drug development.

In this study, a green and efficient enrichment method for the four majors active diterpenoid components: pimelotide C, pimelotide A, simplexin, and 6α,7α-epoxy-5β-hydroxy-12-deoxyphorbol-13-decanoate in the buds of Wikstroemia chamaedaphne was established using macroporous resin chromatography. The adsorption and desorption rates of seven macroporous resins were compared using static tests. The D101 macroporous resin exhibited the best performance. Static and dynamic adsorption tests were performed to determine the enrichment and purification of important bioactive diterpenoids in the buds of W. chamaedaphne. Diterpenoid extracts were obtained by using D101 macroporous resin from the crude extracts of W. chamaedaphne. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis demonstrated that most of the diterpenoids were enriched in diterpenoid extracts. These results confirmed that diterpenoids in the buds of W. chamaedaphne could be enriched using macroporous resin technology, and the enriched diterpenoid extracts showed more efficient activation of the latent human immunodeficiency virus. This study provides a novel strategy for discovering efficient and low-toxicity latency-reversing agents and a potential basis for the comprehensive development and clinical application of the buds of W. chamaedaphne.

Bioinspired skeleton transformation of a tricyclic lathyrane-type Euphorbia diterpene was conducted to efficiently construct a tetracyclic tigliane diterpene on a gram scale via a key aldol condensation. The tigliane diterpene was then respectively converted into naturally rare ingenane and rhamnofolane diterpenes through a semipinacol rearrangement and a visible-light-promoted regioselective cyclopropane ring-opening reaction. This work provides a concise strategy for high-efficiency access to diverse polycyclic Euphorbia diterpene skeletons from abundant lathyrane-type natural products and paves the way for biological activity investigation of naturally rare molecules.

The main focus of this review is to introduce readers to the fascinating class of lipid molecules known as norsteroids, exploring their distribution across various biotopes and their biological activities. The review provides an in-depth analysis of various modified steroids, including A, B, C, and D-norsteroids, each characterized by distinct structural alterations. These modifications, which range from the removal of specific methyl groups to changes in the steroid core, result in unique molecular architectures that significantly impact their biological activity and therapeutic potential. The discussion on A, B, C, and D-norsteroids sheds light on their unique configurations and how these structural modifications influence their pharmacological properties. The review also presents examples from natural sources that produce a diverse array of steroids with distinct structures, including the aforementioned A, B, C, and D-nor variants. These compounds are sourced from marine organisms like sponges, soft corals, and starfish, as well as terrestrial entities such as plants, fungi, and bacteria. The exploration of these steroids encompasses their biosynthesis, ecological significance, and potential medical applications, highlighting a crucial area of interest in pharmacology and natural product chemistry. The review emphasizes the importance of researching these steroids for drug development, particularly in addressing diseases where conventional medications are inadequate or for conditions lacking sufficient therapeutic options. Examples of norsteroid synthesis are provided to illustrate the practical applications of this research.

Glutathione peroxidase 4 (GPX4) is a promising anticancer therapeutic target; however, the application of GPX4 inhibitors (GPX4i) is limited owing to intrinsic or acquired drug resistance. Hence, understanding the mechanisms underlying drug resistance and discovering molecules that can overcome drug resistance are crucial. Herein, we demonstrated that GPX4i killed bladder cancer cells by inducing lipid reactive oxygen species-mediated ferroptosis and apoptosis, and cisplatin-resistant bladder cancer cells were also resistant to GPX4i, representing a higher half-maximal inhibitory concentration value than that of parent bladder cancer cells. In addition, thioredoxin reductase 1 (TrxR1) overexpression was responsible for GPX4i resistance in cisplatin-resistant bladder cancer cells, and inhibiting TrxR1 restored the sensitivity of these cells to GPX4i. In vitro and in vivo studies revealed that Jolkinolide B (JB), a natural diterpenoid and previously identified as a TrxR1 inhibitor, potentiated the antiproliferative efficacy of GPX4i (RSL3 and ML162) against cisplatin-resistant bladder cancer cells. Furthermore, GPX4 knockdown and inhibition could augment JB-induced paraptosis and apoptosis. Our results suggest that inhibiting TrxR1 can effectively improve GPX4 inhibition-based anticancer therapy. A combination of JB and GPX4i, which is well-tolerated and has several anticancer mechanisms, may serve as a promising therapy for treating bladder cancer.

The study entailed the investigation of the roots of Euphorbia wallichii, which resulted in the isolation of 29 ent-atisane diterpenoids (1-29), 14 of which were previously unknown. These previously undescribed ones were named euphorwanoids A-N (3-5, 7, 9, and 10-18). Various techniques, including comprehensive spectroscopic methods and calculated electronic circular dichroism, were employed to determine their molecular structures. Additionally, the absolute configurations of ten ent-atisane diterpenoids (1, 2, 5, 6, 8, 9, 11, 12, 14 and 16) were established through X-ray crystallographic analyses. All isolated compounds' potential to inhibit the influenza A virus in vitro were evaluated. Compounds 18, 20, and 24 exhibited notable antiviral activity against the A/Puerto Rico/8/1934 strain. Their effective concentrations for reducing viral activity (EC50 values) were found to be 8.56, 1.22, and 4.97 μM, respectively. An intriguing aspect of this research is that it marks the first instance of ent-atisane diterpenes displaying anti-H1N1 activity. Empirical NMR rules were established with Δδ to distinguish the R/S configurations of C-13 and C-16 in ent-atisanes.

Premyrsinane-type diterpenoids have been considered to originate from the cyclization of a suitable 5,6- or 6,17-epoxylathyrane precursor. Their biological activities have not been sufficiently explored to date, so the development of synthetic or microbial approaches for the preparation of new derivatives would be desirable. Epoxyboetirane A (4) is an 6,17-epoxylathyrane isolated from Euphorbia boetica in a large enough amount to be used in semi-synthesis. Transannular cyclization of 4 mediated by Cp2TiIIICl afforded premyrsinane 5 in good yield as an only diasteroisomer. To enhance the structural diversity of premyrsinanes so their potential use in neurodegenerative disorders could be explored, compound 5 was biotransformed by Mucor circinelloides NRRL3631 to give rise to hydroxylated derivatives at non-activated carbons (6-7), all of which were reported here for the first time. The structures and absolute configurations of all compounds were determined through extensive NMR and HRESIMS spectroscopic studies.

Lathyrane-type diterpenes have a wide range of biological activities. Among them, euphoboetirane A (1) exerts neurogenesis-promoting activity. In order to increase the structural diversity of this type of lathyrane and explore its potential use in neurodegenerative disorders, the biotransformation of 1 by Streptomyces puniceus BC-5GB.11 has been investigated. The strain BC-5GB.11, isolated from surface sediments collected from the intertidal zone of the inner Bay of Cadiz, was identified as Streptomyces puniceus, as determined by phylogenetic analysis using 16S rRNA gene sequence. Biotransformation of 1 by BC-5GB.11 afforded five products (3-7), all of which were reported here for the first time. The main biotransformation pathways involved regioselective oxidation at non-activated carbons (3-5) and isomerization of the ∆12,13 double bond (6). In addition, a cyclopropane-rearranged compound was found (7). The structures of all compounds were elucidated on the basis of extensive NMR and HRESIMS spectroscopic studies.

The asymmetric total synthesis of pedrolide (>200 mg) with an unprecedented [5-5-5-6-6-3] hexacyclic core (pedrolane) was achieved. Its unique bicyclo[2.2.1]heptane ring system was efficiently constructed via an enantioselective ene reaction of cyclopentadiene followed by a Wittig reaction, isomerization, and a diastereoselective intramolecular Diels-Alder reaction cascade. The highly oxygenated carane [6-3] ring system was synthesized via a ring-closing metathesis reaction followed by an unusual free carbene cyclopropanation. Furthermore, the 12 contiguous stereocenters of pedrolide were installed diastereoselectively.

The question of whether rare 10,11-seco-lathyranes are natural products or artifacts is thoughtfully considered after a Brønsted acid-mediated chemical conversion of naturally abundant 5/11/3 lathyrane type diterpenes into 10,11-seco-lathyranes was developed. Benefiting from this concise route, a series of 10,11-seco-lathyrane products (1-14) were smoothly synthesized. The conversion may involve an acid promoted cyclopropane ring opening accompanied by a double bond shift with final trapping of carbocation. The ease of this chemical conversion under mildly acidic conditions may imply that the 10,11-seco-lathyranes isolated to date are artifacts. This work not only develops a new modular synthetic strategy for efficient constructing rare 10,11-seco-lathyranes, but also provides a promising bioactive diterpene with excellent effect against the NO production on LPS-induced BV-2 cells.

The distribution, chemistry, and molecular bioactivity of tiglianes are reviewed from the very beginning of the studies on these diterpenoids, summarizing their clinical and toxicological literature mostly in its more recent and controversial aspects, and critically analyzing various proposals for their biosynthesis.

The current study was carried out to investigate the anticancer potential of Sauromatum venosum (SV) tuber by gas chromatography with high-resolution mass spectrometry (GC-HRMS) analysis of ethanolic (eSV), hydroalcoholic (hSV), and aqueous extracts (wSV), and in silico study were performed to investigate the main targets of 12-O-acetylingol 8-tiglate by computational docking. The GC-HRMS analysis of three plant samples was carried out on a system equipped with a high-resolution mass spectrometer. The major compounds were identified in all crude extracts. Computation docking analysis was performed for the prediction of the main target of the cancer proliferation of active compound of the Sauromatum venosum tuber extract in cancer therapy. A total of 45 phytocompounds were detected including diterpenoids, esters of fatty acid, hydrocarbons, and alkanes in the tuber of SV. Among all the crude samples tested, eSV showed the lowest IC50 value treated with SaOS2 cells. 12-O-acetylingol 8-tiglate is one of the phytocompounds identified in eSV extract and has been found to exhibit cytotoxic effects against various cancer cells, as reported in the research. It shows the optimum binding affinity with - 8.59 kcal/mol binding energy with a molecular target protein TNF-α (PDB ID: 7PKA). The observed interactions strongly support the anticancer activity of 12-O-acetylingol 8-tiglate and its role in the medicinal efficacy of the plant. These findings highlight the potential of the compound as a valuable source for the development of a therapeutic agent aimed at combating cancer. However, it is important to note that additional in vitro and in vivo studies are required to validate these findings and establish the therapeutic potential.

The number of cancer cases will reach 24 million in 2040, according to the International Agency for Research on Cancer. Current treatments for cancer are not effective and selective for most patients; for this reason, new anticancer drugs need to be developed and researched enough. There are potentially useful drugs for cancer isolated from plants that are being used in the clinic. Available information about phytochemistry, traditional uses, in vitro and in vivo experiments with plants, and pure compounds isolated from the Euphorbiaceae family indicates that this family of plants has the potential to develop anticancer drugs. This review examines selected species from the Euphorbiaceae family and their bioactive compounds that could have potential against different types of cancer cells. It reviews the activity of crude extracts, isolated compounds, and nanoparticles and the potential underlying mechanisms of action.

Thirteen new Euphorbia diterpenoids, euphylonanes A-M (1-13), and eight known ones were isolated from the whole plants of Euphorbia hylonoma. Compounds 1 and 2 are two rearranged ingenanes bearing a rare 6/6/7/3-fused ring system. Compound 3 represents the first example of a 9,10-epoxy tigliane, while 4-21 are typical ingenanes varying with substituents. Structures were elucidated using a combination of spectroscopic, computational, and chemical methods. Most ingenanes exerted a significant antiadipogenic effect in 3T3-L1 adipocytes, among which 4 was the most active with an EC50 value of 0.60 ± 0.27 μM. Mechanistic study revealed that 4 inhibited the adipogenesis and lipogenesis in adipocytes via activation of the AMPK signaling pathway.

Euphorbia species are important sources of polycyclic and macrocyclic diterpenes, which have been the focus of natural-product-based drug research due to their relevant biological properties, including anticancer, multidrug resistance reversal, antiviral, and anti-inflammatory activities. Premyrsinane, cyclomyrsinane, and myrsinane diterpenes are generally and collectively designated as myrsinane-type diterpenes. These compounds are derived from the macrocyclic lathyrane structure and are characterized by having highly oxygenated rearranged polycyclic systems. This review aims to describe and summarize the distribution and diversity of 220 myrsinane-type diterpenes isolated in the last four decades from about 20 Euphorbia species. Some myrsinane diterpenes obtained from Jatropha curcas are also described. Discussion on their plausible biosynthetic pathways is presented, as well as isolation procedures and structural elucidation using nuclear magnetic resonance spectroscopy. Furthermore, the most important biological activities are highlighted, which include cytotoxic and immunomodulatory activities, the modulation of efflux pumps, the neuroprotective effects, and the inhibition of enzymes such as urease, HIV-1 reverse transcriptase, and prolyl endopeptidase, among other biological effects.

Euphorbia diterpenoids possess inhibitory effects of Kv1.3 ion channel, but most of this research has focused on diterpenoids with jatrophane-related or ingenane-related skeletons. In the present study, nine undescribed (1-9) and 16 known (10-25) diterpenoids, based on jatrophane, lathyrane, ingenane, abietane, and atisane skeletons, were identified from the methanol extract of the aerial parts of Euphorbia fischeriana. The structures were established by analysis of the spectroscopic data as well as by single-crystal X-ray diffraction analysis. Among the isolated diterpenoids, macrocyclic jatrophanes and lathyranes exerted Kv1.3 blocking activity. Compound 8 exhibited good selectivity on the inhibition of the Kv 1.3 channel rather than hERG channel, with a selectivity index over 7.0. The selective activity of lathyrane diterpenoids indicates that macrocyclic diterpenoids have the potential to be further investigated as therapeutic agents for the treatment of autoimmune diseases.

The naturally scarce eupholathone-type euphornin E (1) was efficiently prepared from abundant lathyrane-type Euphorbia factor L1via a visible-light-induced Sc(OTf)3-catalyzed tandem process. Eupholathones 2 and 3 were also smoothly obtained by changing the reaction solvent. This route provides a convenient method for easily constructing scarce eupholathone- from lathyrane-type Euphorbia diterpenes, and confirms the biogenetic relationship between them from a chemical standpoint. Notably, compound 1 exhibited good anti-HIV activity.

Covering: 2018 to 2022Meroterpenoids found in fungal species of the genus Ganoderma and known as Ganoderma meroterpenoids (GMs) are substances composed of a 1,2,4-trisubstituted benzene and a polyunsaturated side chain. These substances have attracted the attention of chemists and pharmacologists due to their diverse structures and significant bioactivity. In this review, we present the structures and possible biosynthesis of representative GMs newly found from 2018 to 2022, as well as chemical synthesis and biological activity of some interesting GMs. We propose for the first time a plausible biosynthetic pathway for GMs, which will certainly motivate further research on the biosynthetic pathway in Ganoderma species, as well as on chemical synthesis of GMs as important bioactive compounds for the purpose of drug development.

The roots of the plant Euphorbia ebracteolata Hayata (Yue Xian Da Ji) are commonly used in traditional Chinese medicine to treat multiple diseases such as chronic liver diseases, oedema, pulmonary diseases and cancer. It is the main ingredient of the TCM called Langdu which can be prepared also from roots of E. fischeriana Steud. and occasionally from Stellera chamaejasme species. Numerous bioactive natural products have been isolated from E. ebracteolata including a large diversity of diterpenoids with anti-inflammatory and anticancer properties. One little series of compounds has been named yuexiandajisu (A, B, C, D, D₁, E, F) which comprises two casbane-, one isopimarane-, two abietane-, and two rosane-type diterpenes including a dimeric molecule. The origin, structural diversity and properties of these little-known natural products is discussed here. Several of these compounds have been identified in the roots of other Euphorbia species, notably the potent phytotoxic agent yuexiandajisu C. The abietane diterpenes yuexiandajisu D-E exhibit marked anticancer properties but their mechanism of action remains unresolved. The dimeric compound, renamed yuexiandajisu D₁, also exhibit anti-proliferative properties against cancer cell lines, unlike the rosane diterpene yuexiandajisu F. The structural or functional analogy with other diterpenoids is discussed.

Nine undescribed diterpenoids, euphlactenoids A-I (1-9), including four ingol-type diterpenoids (1-4) with a 5/3/11/3-tetracyclic framework and five ent-pimarane-type diterpenoids (5-9), together with thirteen known diterpenoids (10-22), were identified from the leaves and stems of Euphorbia lactea Haw. The structures and absolute configurations of compounds 1-9 were unequivocally elucidated on the basis of spectroscopic analysis, ECD calculations and single crystal X-ray diffraction. Compounds 3 and 16 showed anti-HIV-1 effects with IC₅₀ values of 1.17 μM (SI = 16.54) and 13.10 μM (SI = 1.93), respectively.

Four previously undescribed highly oxygenated diterpenoids (1-4), zeylleucapenoids A-D, characterized by halimane and labdane skeletons, were isolated from the aerial parts of Leucas zeylanica. Their structures were elucidated primarily via NMR experiments. The absolute configuration of 1 was established using theoretical ECD calculations and X-ray crystallographic analysis, whereas those for 2-4 were assigned using theoretical ORD calculations. Zeylleucapenoids A-D were tested for anti-inflammatory activity against nitric oxide (NO) production in RAW264.7 macrophages, of which only 4 showed significant efficacy with an IC₅₀ value of 38.45 μM. Further, active compound 4 was also evaluated for the inhibition of the release of pro-inflammatory cytokines TNF-α and IL-6 and was found to have a dose-dependent inhibitory effect, while it showed nontoxic activity for zebrafish embryos. A subsequent Western blotting experiment revealed that 4 inhibited the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Furthermore, molecular docking analysis indicated that the possible mechanism of action for 4 may be bind to targets via hydrogen and hydrophobic bond interactions.

Phytochemical investigations on the ethanol extract of the whole plant of Euphorbia maculata Linn. Resulted in the identification of 16 lanostane-related triterpenoids, including 11 undescribed ones, namely spiromaculatols A-C (1-3) and euphomaculatoids A-H (4-11). The structural determinations of the previously undescribed ones (1-11) were elucidated based on the interpretation of comprehensive spectroscopic data, quantum chemical calculation, as well as X-ray crystallographic experiments. Spiromaculatols A-C (1-3) possess a rare spirobi [indane] skeleton, which was biosynthetically derived from the 7 (8 → 9)-abeo bond migration of lanostane precursors. The biological activity of compounds 1-3, 5, 7, and 12-13 displayed inhibitory effect on the release of NO in an LPS-activated RAW264.7 cells model. Molecular mechanism study indicated that the most potent spiromaculatol C (3) can reduce the nuclear translocation of NF-κB p65 and decrease the transcriptional expressions of its downstream pro-inflammatory mediators.

Two rearranged norditerpenoids with novel tricyclic carbon skeletons, strophiofimbrin A (1) and strophiofimbrin B (2), were isolated from Strophioblachia fimbricalyx. Their structures were established by 1D/2D NMR spectroscopy, HRESIMS, quantum chemistry calculations, and X-ray diffraction analyses. 1 and 2 represented the first examples of diterpenoids with unprecedented 5/6/7-fused ring systems. In the proposed biosynthetic pathway, they were suspected to derive from cleistanthane norditerpenoids via ring opening, expansion, cyclization, and rearrangement based on the existence of phenanthrenone and cleistanthane diterpenoids from Strophioblachia and Trigonostemon, two closely related genera of the Euphorbiaceae family. Furthermore, compounds 1 and 2 exhibited significant proliferation inhibition and obvious neuroprotective effects.

The first total synthesis of (+)-pedrolide, a tigliane-derived diterpenoid featuring an unprecedented 5-5-6-6-3 carbon skeleton, is reported. Key to the approach is the construction of the bicyclo[2.2.1]heptane core via an intramolecular cyclopentadiene-Diels-Alder cycloaddition. To this end, a norbornadiene serves as an effective surrogate for cyclopentadiene, which is unmasked under mild conditions involving a complex Diels-Alder reaction cascade. In addition, the synthesis provides a novel approach to a densely functionalized carane in an efficient and enantioselective manner.

The biorelevant sulfur-containing Euphorbia diterpenes with scarce 5/7/6/3 premyrsinane- and 5/7/6 myrsinane-type backbones were easily constructed from naturally abundant lathyrane-type Euphorbia factor L₃ by visible-light-triggered tandem thiol-ene click reaction/transannular cyclization and regioselective cyclopropane ring-opening. The selenide diterpene was also successfully obtained to verify the system universality. This concise synthesis route gives an efficient strategy for obtaining structurally diverse Euphorbia diterpenes under very mild conditions and provides a promising anti-HIV bioactive premyrsinane diterpene 3h.

In spite of tremendous efforts exerted in the management of COVID-19, the absence of specific treatments and the prevalence of delayed and long-term complications termed post-COVID syndrome still urged all concerned researchers to develop a potent inhibitor of SARS-Cov-2. The hydromethanolic extracts of different parts of E. mauritanica were in vitro screened for anti-SARS-Cov-2 activity. Then, using an integrated strategy of LC/MS/MS, molecular networking and NMR, the chemical profile of the active extract was determined. To determine the optimum target for these compounds, docking experiments of the active extract's identified compounds were conducted at several viral targets. The leaves extract showed the best inhibitory effect with IC₅₀ 8.231±0.04 μg/ml. The jatrophane diterpenes were provisionally annotated as the primary metabolites of the bioactive leaves extract based on multiplex of LC/MS/MS, molecular network, and NMR. In silico studies revealed the potentiality of the compounds in the most active extract to 3CLpro, where compound 20 showed the best binding affinity. Further attention should be paid to the isolation of various jatrophane diterpenes from Euphorbia and evaluating their effects on SARS-Cov-2 and its molecular targets.

A series of lathyrane-type Euphorbia diterpene derivatives featured 3R configuration (H-3β) were synthesized from natural rich Euphorbia factor L₃via modified Mitsunobu reaction based on configuration inversion strategy. The antiproliferation activity and MDR reversal ability of the lathyrane derivatives were evaluated, and the most synthesized compounds showed moderate or strong potencies. Among them, diterpenes 21 (IC₅₀ values of 2.6, 5.2 and 13.1 μM, respectively) and 25 (IC₅₀ values of 5.5, 8.6 and 1.3 μM, respectively) presented the strong cytotoxicity against MCF-7, 4 T1 and HepG2 cells. Meanwhile, derivative 25 exhibited excellent MDR reversal ability with the reversal fold of 16.1 higher than that of verapamil. The cellular thermal shift assay and molecular docking proved direct engagement of diterpene 25 to ABCB1, suggesting 25 could be a promising MDR modulator. Furthermore, the preliminary SARs of these diterpenes were also discussed.

Glochidpurnoids A and B (1 and 2), two new coumaroyl or feruloyl oleananes, along with 17 known triterpenoids (3-19) were obtained from the stems and twigs of Glochidion puberum. Their structures were elucidated by extensive spectroscopic data analyses, chemical methods, and single crystal X-ray diffraction. All compounds were screened for cytotoxicity against the colorectal cancer cell line HCT-116, and 2, 3, 5, 6, 11, and 17 showed remarkable inhibitory activities (IC₅₀: 0.80-2.99 μM), being more active than the positive control 5-fluorouracil (5-FU). The mechanistic study of 2, the most potent compound, showed that it could induce endoplasmic reticulum (ER) stress-mediated apoptosis and improve the sensitivity of HCT-116 cells to 5-FU.

Euphylonoids A (1) and B (2), two highly modified jatrophane diterpenoids, were isolated from Euphorbia hylonoma. 1 represents a new 9(10→18)-abeo-8,12-cyclojatrophane skeleton containing a cage-like 3,8-dioxatricyclo[5.1.2.0^4,9]decane core, while 2 is a 14(13→20)-abeo-8,12-cyclojatrophane featuring an unusual 17-oxatetracyclo[12.2.1.0^1,5.0^9,13]heptadecane framework. Their structural elucidation was completed by spectroscopic, chemical, computational, and single-crystal X-ray diffraction means. 2 significantly inhibited early adipogenesis in 3T3-L1 adipocytes via activating AMP-activated protein kinase signaling.