Diterpenoid honatisine overcomes temozolomide resistance in glioblastoma by inducing mitonuclear protein imbalance through disruption of TFAM-mediated mtDNA transcription.

BACKGROUND: Glioblastoma (GBM) represents as the most formidable intracranial malignancy. The systematic exploration of natural compounds for their potential applications in GBM therapy has emerged as a pivotal and fruitful avenue of research. PURPOSE: In the present study, a panel of 96 diterpenoids was systematically evaluated as a repository of potential antitumour agents. The primary objective was to discern their potency in overcoming resistance to temozolomide (TMZ). Through an extensive screening process, honatisine, a heptacyclic diterpenoid alkaloid, emerged as the most robust candidate. Notably, honatisine exhibited remarkable efficacy in patient-derived primary and recurrent GBM strains. Subsequently, we subjected this compound to comprehensive scrutiny, encompassing GBM cultured spheres, GBM organoids (GBOs), TMZ-resistant GBM cell lines, and orthotopic xenograft mouse models of GBM cells. RESULTS: Our investigative efforts delved into the mechanistic underpinnings of honatisine's impact. It was discerned that honatisine prompted mitonuclear protein imbalance and elicited the mitochondrial unfolded protein response (UPRmt). This effect was mediated through the selective depletion of mitochondrial DNA (mtDNA)-encoded subunits, with a particular emphasis on the diminution of mitochondrial transcription factor A (TFAM). The ultimate outcome was the instigation of deleterious mitochondrial dysfunction, culminating in apoptosis. Molecular docking and surface plasmon resonance (SPR) experiments validated honatisine's binding affinity to TFAM within its HMG-box B domain. This binding may promote phosphorylation of TFAM and obstruct the interaction of TFAM bound to heavy strand promoter 1 (HSP1), thereby enhancing Lon-mediated TFAM degradation. Finally, in vivo experiments confirmed honatisine's antiglioma properties. Our comprehensive toxicological assessments underscored its mild toxicity profile, emphasizing the necessity for a thorough evaluation of honatisine as a novel antiglioma agent. CONCLUSION: In summary, our data provide new insights into the therapeutic mechanisms underlying honatisine's selective inducetion of apoptosis and its ability to overcome chemotherapy resistance in GBM. These actions are mediated through the disruption of mitochondrial proteostasis and function, achieved by the inhibition of TFAM-mediated mtDNA transcription. This study highlights honatisine's potential as a promising agent for glioblastoma therapy, underscoring the need for further exploration and investigation.

Degradable carrier-free spray hydrogel based on self-assembly of natural small molecule for prevention of postoperative adhesion.

Postoperative peritoneal adhesion (PPA) is frequent and extremely dangerous complication after surgery. Different tactics have been developed to reduce it. However, creating a postoperative adhesion method that is multifunctional, biodegradable, biocompatible, low-toxic but highly effective, and therapeutically applicable is still a challenge. Herein, we have prepared a degradable spray glycyrrhetinic acid hydrogel (GAG) based on natural glycyrrhetinic acid (GA) by straightforward heating and cooling without the use of any additional chemical cross-linking agents to prevent postoperative adhesion. The resultant hydrogel was demonstrated to possess various superior anti-inflammatory activity, and multiple functions, such as excellent degradability and biocompatibility. Specifically, spraying characteristic and excellent antibacterial activities essentially eliminated secondary infections during the administration of drugs in surgical wounds. In the rat models, the carrier-free spray GAG could not only slow-release GA to inhibit inflammatory response, but also serve as physical anti-adhesion barrier to reduce collagen deposition and fibrosis. The sprayed GAG would shed a new light on the prevention of postoperative adhesion and broaden the application of the hydrogels based on natural products in biomedical fields.

Four Meroterpenoids with Novel Aminoglycoside Moiety from the Basidiomycete Clitocybe clavipes with Cytotoxic Activity.

Four new meroterpenoids, Clavilactone M-P, possessing novel aminoglycoside moiety (1-4) and a 10-membered carbocycle fused with an α,ß-epoxy-γ-lactone, were isolated from Clitocybe clavipes, a basidiomycete. Their structures with absolute configurations were determined by extensive analysis of their spectroscopic data, and the ECD method. All the isolated compounds (1-4) were evaluated for their antitumor activity against three human cancer cell lines using the MTT assay. Compound 1 and 2 exhibited a significant suppression of cell viability in the Hela (IC50 = 22.8 and 19.7 µM) cell line.

A novel nonreversible heat-induced low-molecular-weight gel based on naturally-occurring self-assembled fupenzic acid for tumor therapy.

Herein, a nonreversible heat-induced supramolecular gel based on natural products was reported for the first time. This natural triterpenoid, fupenzic acid (FA), isolated from the roots of Rosa laevigata, was discovered to be capable of forming supramolecular gel spontaneously in 50 % ethanol-water solution induced by heating. Distinguished from the common thermosensitive gels, the FA-gel showed a distinctive nonreversible phase transition from the liquid to gel state upon heating. In this work, the entire gelation process of FA-gel induced by heating was recorded digitally by microrheology monitor. And a unique heat-induced gelation mechanism based on self-assembled FA has been proposed by using various experimental methods and molecular dynamics (MD) simulation. Its excellent injectability and stability were also demonstrated. Furthermore, the FA-gel had been evaluated to exhibit better anti-tumor activity and higher biosafety comparing with its equivalent free-drug, which opened up a new possibility to reinforce antitumor efficacy by using natural product gelator originated from traditional Chinese medicine (TCM) without any complicated chemical modifications.

Natural carrier-free self-assembled diterpene nanoparticles with its efficient anti-inflammation through the inhibition of NF-κB pathway for accelerated wound healing.

Nanoscience has set off a wave in biomedicine to improve the performance of drugs in recent years, but additional materials are usually required for supramolecular nanoconstruction, undoubtedly increasing the health risks. Herein, we discovered a novel diterpene supramolecular self-assembly system without additional chemicals, Nepebracteatalic Acid nanoparticles (NA NPs), mediated through hydrogen bond, hydrophobic and electrostatic interaction. NA NPs performed sustained release behavior, lower expression levels for IL-6 and TNF-α than clinical anti-inflammatory drug Indometacin. Furthermore, the effect of NA NPs on the related protein p65 expression levels of nuclear factor-κB (NFκB) signaling pathway is quantified to confirm the enhanced anti-inflammatory property based on the self-assembly strategy. Meanwhile, the prepared nanoparticles have good biocompatibility which ensures outstanding inflammation inhibition, collagen deposition, angiogenesis during wound healing. This work opens up new prospects that carrier-free nanoparticles from NPMs have great potential to exert clinical application value, meanwhile providing reference for developing green nanoscience.

Cucurbitacin IIb Extracted from Hemsleya penxianensis Induces Cell Cycle Arrest and Apoptosis in Bladder Cancer Cells by Regulating Cell Cycle Checkpoints and Mitochondrial Apoptotic Pathway.

Cucurbitacin IIb (CuIIb) extracted from Hemsleya penxianensis has been demonstrated anticancer activity in many malignancies, however, its effect against bladder cancer cells and the molecular mechanism remains unclear. Accordingly, in the present study, we evaluated the effect and further the underlying mechanism of CuIIb on bladder cancer cells. Cell viability and clonogenicity were examined to evaluate growth suppressive effect of CuIIb, alongside mechanism exploration was conducted based on RNA sequencing (RNA-seq). The results showed that CuIIb exposure inhibited the growth of T24 and UM-UC-3 bladder cancer cells as indicated by its obvious suppression on cell viability and clonogenicity. Mechanistic studies by RNA-seq and quantifying analysis of RNA-seq data by TMNP indicated cell cycle modulated by cell cycle checkpoints and apoptosis mediated by PI3K/Akt pathway might account for the anticancer activity of CuIIb. Consistently, results of flow cytometry and AO/EB staining demonstrated that the growth-suppressive effect of CuIIb was mediated by cell cycle arrest in G2/M phase and robust induction of cell apoptosis, which was further confirmed by immunoblotting and mitochondrial membrane potential (ΔΨm) analysis. Collectively, the results presented herein indicated that CuIIb exhibited anticancer activity on bladder cancer which may be a potential candidate for improving bladder cancer outcomes.

Increasing brain glucose uptake by Gypenoside LXXV ameliorates cognitive deficits in a mouse model of diabetic Alzheimer's disease.

We have previously reported that Gypenoside LXXV (GP-75), a novel natural PPARγ agonist isolated from Gynostemma pentaphyllum, ameliorated cognitive deficits in db/db mice. In this study, we further investigated the beneficial effects on cognitive impairment in APP/PS1 mice and a mouse model of diabetic AD (APP/PS1xdb/db mice). Interestingly, intragastric administration of GP-75 (40 mg/kg/day) for 3 months significantly attenuated cognitive deficits in APP/PS1 and APP/PS1xdb/db mice. GP-75 treatment markedly reduced the levels of glucose, HbA1c and insulin in serum and improved glucose tolerance and insulin sensitivity in APP/PS1xdb/db mice. Notably, GP-75 treatment decreased the ß-amyloid (Aß) burden, as measured by 11 C-PIB PET imaging. Importantly, GP-75 treatment increased brain glucose uptake as measured by 18 F-FDG PET imaging. Moreover, GP-75 treatment upregulated PPARγ and increased phosphorylation of Akt (Ser473) and GLUT4 expression levels but decreased phosphorylation of IRS-1 (Ser616) in the hippocampi of both APP/PS1 and APP/PS1xdb/db mice. Furthermore, GP-75-induced increases in GLUT4 membrane translocation in primary hippocampal neurons from APP/PS1xdb/db mice was abolished by cotreatment with the selective PPARγ antagonist GW9662 or the PI3K inhibitor LY294002. In summary, GP-75 ameliorated cognitive deficits in APP/PS1 and APP/PS1xdb/db mice by enhancing glucose uptake via activation of the PPARγ/Akt/GLUT4 signaling pathways.

Two new cycloartane triterpenoid glycosides from the rhizomes of Actaea vaginata.

Two new cycloartane triterpenoid glycosides, soulieoside V (1) and 15-deacetylbeesioside O (2), together with one known compound, beesioside J (3), were isolated from the ethanolic extract of the rhizomes of Actaea vaginata. Their structures were elucidated by spectroscopic methods and by comparison with data reported in the literature. All the compounds were tested for their cytotoxic activities against human cancer cell lines.

Cyclohexene oxide CA, a derivative of zeylenone, exhibits anti-cancer activity in glioblastoma by inducing G0/G1 phase arrest through interference with EZH2.

Introduction: Due to its highly aggressiveness and malignancy, glioblastoma (GBM) urgently requires a safe and effective treatment strategy. Zeylenone, a natural polyoxygenated cyclohexenes compound isolated from Uvaria grandiflora, has exhibited potential biological activities in various human diseases, including tumors. Methods: We designed and synthesized a series of (+)-Zeylenone analogues and evaluated their anti-GBM roles through structural-activity analysis. Cell Counting Kit-8, TUNEL, transwell and flow cytometry were employed for investigating the anticancer effects of CA on GBM cells. Western blotting, molecular docking, qRT-PCR and ChIP assays were performed to reveal the underlying mechanisms by which CA regulates the GBM cell cycle. The nude mouse xenograft model, HE staining, immunohistochemistry and was used to evaluate the anticancer effect of CA in vivo. Results: We identified CA ((1R, 2R, 3S)-3-p-fluorobenzoyl-zeylenone) as having the lowest IC50 value in GBM cells. CA treatment significantly inhibited the malignant behaviors of GBM cells and induced G0/G1 phase arrest in vitro. Furthermore, we validated the molecular mechanism by which CA interferes with EZH2, attenuating the down-regulation of cyclin-dependent kinase inhibitors p27 and p16 by the PRC2 complex. By establishing orthotopic nude mice models, we further validated the inhibitory role of CA on tumorigenesis of GBM cells in vivo and its potential values to synergistically potentiate the anti-tumor effects of EZH2 inhibitors. Conclusion: Overall, this paper elucidated the anti-GBM effects and potential mechanisms of CA, and may provide a therapeutic drug candidate for GBM treatment.

Increasing brain glucose metabolism by ligustrazine piperazine ameliorates cognitive deficits through PPARγ-dependent enhancement of mitophagy in APP/PS1 mice.

PPARγ agonists have been proven to be neuroprotective in vitro and in vivo models of Alzheimer's disease (AD). In the present study, we identified ligustrazine piperazine derivative (LPD) as a novel PPARγ agonist, which was detected by a dual-luciferase reporter assay system. LPD treatment dose-dependently reduced Aß40 and Aß42 levels in PC12 cells stably transfected with APP695swe and PSEN1dE9. Intragastric administration of LPD for 3 months dose-dependently reversed cognitive deficits in APP/PS1 mice. LPD treatment substantially decreased hippocampal Aß plaques in APP/PS1 mice and decreased the levels of Aß40 and Aß42 in vivo and in vitro. Moreover, LPD treatment induced mitophagy in vivo and in vitro and increased brain 18F-FDG uptake in APP/PS1 mice. LPD treatment significantly increased OCR, ATP production, maximal respiration, spare respiratory capacity, and basal respiration in APP/PS1 cells. Mechanistically, LPD treatment upregulated PPARγ, PINK1, and the phosphorylation of Parkin (Ser65) and increased the LC3-II/LC3-I ratio but decreased SQSTM1/p62 in vivo and in vitro. Importantly, all these protective effects mediated by LPD were abolished by cotreatment with the selective PPARγ antagonist GW9662. In summary, LPD could increase brain glucose metabolism and ameliorate cognitive deficits through PPARγ-dependent enhancement of mitophagy in APP/PS1 mice.

Comparison of the Effects of Open Surgery and Minimally Invasive Surgery on the Achilles Tendon Rupture Healing Based on Angiogenesis.

Objective: To compare the effect of three different surgical methods on rabbit Achilles tendon rupture. Methods: The Achilles tendon transection model was constructed by cutting off the inner half of the Achilles tendon. Rabbits were divided into 4 groups: model group, open surgery (OS) group, minimally invasive surgery (MS) group, and conservative treatment (CT) group. Biomechanical evaluation, H&E, and Picrosirius Red staining were applied to evaluate the histological changes and healing. RT-qPCR, Western blot, ELISA, and IHC staining were used to detect the expression of COLIII, IL-1ß, TNF-α, IL-6, CD31, VEGF, bFGF, and TGF-ß1. Results: Different surgery treatments significantly alleviated the histological changes in rabbits. The tension and elasticity of the Achilles tendon were significantly increased after surgery. In addition, surgery treatments notably alleviated the inflammatory responses in vivo via downregulation of IL-1ß, TNF-α, and IL-6 and promoted the tube formation in tissues through upregulating VEGF, bFGF, TGF-ß1, and CD31. Furthermore, MS exhibited best therapeutic efficiency on Achilles tendon rupture healing, compared with OS or CT. Conclusions: Our research revealed the superiority of MS in Achilles tendon rupture treatment at the molecular level compared with OS or CT.

Daphnane-Type Diterpenes from Stelleropsis tianschanica and Their Antitumor Activity.

Four new daphnane-type diterpenes named tianchaterpenes C-F (1-4) and six known ones were isolated from Stelleropsis tianschanica. Their structures were elucidated based on chemical and spectral analyses. The comparisons of calculated and experimental electronic circular dichroism (ECD) methods were used to determine the absolute configurations of new compounds. Additionally, compounds 1-10 were evaluated for their cytotoxic activities against HGC-27 cell lines; the results demonstrate that compound 2 had strong cytotoxic activities with IC50 values of 8.8 µM, for which activity was better than that of cisplatin (13.2 ± 0.67 µM).

Cytotoxic cycloartane triterpenoid saponins from Actaea vaginata and their mechanism of action.

A further phytochemical investigation of the whole plants of Actaea vaginata afforded two new cycloartane triterpenoid saponins, (20S*,24R*)-15α,16ß-diacetoxy-20,24-epoxy-9,19-cyclolanostane-3ß,25-diol-3-O-ß-d-xylopyranoside (1) and (20S)-15ß,16ß -diacetoxy-18,20-epoxy-3ß,25-diol-24-oxo-9,19-cyclolanostan-3-O-ß-D-xylo-pyrano-syl-25-O-ß-d-glucopyranoside (2), together with four known compounds (3-6). Their structures were established on the basis of extensive analysis of NMR and HRESIMS data as well as by comparison with the reported data in the literature. All the isolates were evaluated for their cytotoxic activities against human hepatocellular carcinoma HepG2 cell line. Compounds 1 and 2 exhibited weak cytotoxicity with IC50 values of 36.10 and 27.39 µM, respectively. In addition, beesioside I (6) was found to significantly inhibit proliferation and induce apoptosis in HepG2 cells. A closer examination of underlying mechanism revealed that beesioside I could increase the levels of ROS and caspase-3 and promote phosphorylation of JNK in the JNK signaling pathway. Molecular modeling studies also shed further light on how beesioside I interacted with the key protein kinase.

Novel geranylhydroquinone derived meroterpenoids from the fungus Clitocybe clavipes and their cytotoxic activity.

Three novel geranylhydroquinone derived meroterpenoids, named clavilactones J and K (1-2) and clavipol C (3), were isolated from the basidiomycete Clitocybe clavipes. Their structures were unambiguously identified by extensive spectroscopic data analysis, and the electronic circular dichroism (ECD) calculation, Gauge-Including Atomic Orbitals (GIAO) NMR calculations and Mo2(OAc)4-induced electronic circular dichroism experiments were used to establish their absolute configurations. Compound 1, with two epoxy groups located at the 10-membered carbocycle, is uncommon in the reported meroterpenoids from C. clavipes. All the obtained compounds (1-3) were tested for their cytotoxic activity against human tumor cell line HGC-27 by using the MTT assay. All the compounds exhibited moderate cytotoxic activities against HGC-27 cell with IC50 values ranging from 33.5 to 56.6 µM.

MiR-192-5p Alleviated Fibrosis and Inflammatory Responses of Tendon Cells by Targeting NFAT5.

Objective: To explore the effect of microRNA (miR)-192-5p on the inflammatory and fibrotic responses of tendon cells. Methods: Tendon cells were treated with transforming growth factor-ß1 (TGF-ß1). The expression of miR-192-5p and nuclear factor of activated T cells 5 (NFAT5) in tendon cells were detected by RT-qPCR. The expressions of inflammatory and fibrosis-related factors were detected by RT-qPCR and Western blot. MiR-192-5p binds to NFAT5 targeting by TargetScan and dual-luciferase reporter gene assay. The expression of the NFAT5 gene was detected by RT-qPCR and Western blot. Detection of apoptosis in tendon cells by flow cytometry. Results: MiR-192-5p was downregulated in tendon cells, and the expression level gradually decreased with the prolong of TGF-ß1 treatment. The expression of NFAT5 increased with the treatment time of TGF-ß1. The expression of miR-192-5p decreased collagen III (COLIII), α smooth muscle actin (α-SMA), matrix metalloproteinase- (MMP-) 1, and MMP-8 expression, thereby inhibiting TGF-ß1-induced fibrosis in tendon cells. The expression of miR-192-5p decreased the expression of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1ß, thereby alleviating TGF-ß1-induced inflammatory response and reduce apoptosis in tendon cells. NFAT5 is a direct target of miR-192-5p in tendon cells. The upregulation of NFAT5 reversed the effect of miR-192-5p on the fibrotic activity and inflammatory response of TGF-ß1-stimulated tendon cells. Conclusions: MiR-192-5p alleviates fibrosis and inflammatory responses of tendon cells by targeting NFAT5.

Cucurbitane triterpenoid entities derived from Hemsleya penxianensis triggered glioma cell apoptosis via ER stress and MAPK signalling cross-talk.

In the present study, six new cucurbitane type compounds, including three triterpenoids hemsleyacins P-R (6-7, 13) and three cucurbitane-type triterpenoid glycosides hemsleyaosides L-N (15-17), along with seventeen known cucurbitacin analogues were separated from the root tuber of Hemsleya penxianensis and elucidated based on NMR and HRESIMS. Then, 23 analogues of three types, namely, polyhydroxy-type (I) (1-7), monohydroxy-type (II) (8-13), and glycosides-type (III) (14-23), were assessed for their antitumor activity and structure-activity relationship analysis (SAR). We determined temozolomide (TMZ)-resistant GBM cell was the most sensitive to the tested compounds, and found hemsleyaoside N (HDN) displayed the best antineoplastic potency. Furthermore, we confirmed the anti-glioma activity of HDN in patient-derived recurrent GBM strains, GBM organoid (GBO) and orthotopic nude mouse models. Investigations exploring the mechanism made clear that HDN induced synchronous activation of UPR and MAPK signaling, which triggered deadly ER stress and apoptosis. Taken together, the potent antitumor activity of HDN warrants further comprehensive evaluation as a novel anti-glioma agent.

Cadinane-type sesquiterpenoid dimeric diastereomers hibisceusones A-C from infected stems of Hibiscus tiliaceus with cytotoxic activity against triple-negative breast cancer cells.

Three new cadinane-type sesquiterpenoid dimeric diastereomers (1-3) named hibisceusones A-C were obtained from the infected stems of Hibiscus tiliaceus. The structures were determined by NMR spectroscopy and MS techniques, and the absolute configurations were assigned by ECD and single-crystal X-ray diffraction techniques. Compounds 1-3 are diastereomers, and contain a 1,4-dioxane ring linearly fused to different cadinane-type polycyclic skeletons. This is the first time that such a structure has been identified in natural products. Compounds 1-3 exhibited cytotoxic activities, and 2 showed a significantly high anti-triple-negative breast cancer (TNBC) effect. The anti-cancer effect of compound 2 was 3-4 fold higher than that of 1 and 3. The anti-cancer effect was generated via the induction of the apoptosis of the MDA-MB-231 cells by inhibiting the PI3Kα pathway.

Novel Triterpenoid Alkaloids With Their Potential Cytotoxic Activity From the Roots of Siraitia grosvenorii.

Four novel triterpenoid alkaloids, siragrosvenins A-D (1-4), and two new cucurbitane-type triterpenoids, siragrosvenins E-F (5, 6), together with eight known analogs (7-14), were isolated from the roots of Siraitia grosvenorii. Compounds 1-4 possessed a rare cucurbitane-type triterpenoid scaffold, featuring an extra pyrazine unit via the Strecker reaction in the cucurbitane framework. Compound 5 displayed a 6/6/6/5/6/5-fused polycyclic ring system, with an uncommon fused furan and pyran ring in the side chain. All the structures were characterized by extensive spectroscopic analysis, including HRESIMS, NMR, and X-ray crystallographic data. It is worth noting that the DP4+ analysis method was applied for the first time to determine the absolute configurations of the trihydroxybutyl moiety in the side chain of compounds 1-4. In vitro cytotoxicity screening found that compounds 4, 8, 9, 13, and 14 exhibited remarkable cytotoxic activities against three cell lines with IC50 values ranging from 1.44 to 9.99 µM. Siragrosvenin D shows remarkable cytotoxic activity on MCF-7 cells. As a result, it inhibited the proliferation of MCF-7 cells and reduced their viability via the induction of G2/M phase arrest and significantly induced apoptosis in MCF-7 cells.

A novel natural PPARγ agonist, Gypenoside LXXV, ameliorates cognitive deficits by enhancing brain glucose uptake via the activation of Akt/GLUT4 signaling in db/db mice.

Targeting the PPARγ might be a potential therapeutic strategy for diabetes-associated cognitive decline (DACD). In this study, Gypenoside LXXV (GP-75), a dammarane-type triterpene compound isolated from Gynostemma pentaphyllum, was found to be a novel PPARγ agonist using a dual-luciferase reporter assay system. However, whether GP-75 has protective effects against DACD remains unknown. Interestingly, intragastric administration of GP-75 (40 mg/kg/day) for 12 weeks significantly attenuated the cognitive deficit in db/db mice. GP-75 treatment significantly improved the glucose tolerance and lipid metabolism, and suppressed neuroinflammation. Notably, GP-75 treatment dramatically increased the uptake of glucose by the brain, as detected by 18 F-FDG PET. Incubation of primary cortical neurons with GP-75 significantly increased 2-deoxyglucose uptake. In addition, GP-75 treatment markedly increased the p-Akt (Ser 473)/total Akt levels and the expression levels of PPARγ and GLUT4, while decreasing the levels of p-IRS-1 (Ser 616)/total IRS-1. Importantly, all of these protective effects mediated by GP-75 were abolished by cotreatment with the PPARγ antagonist, GW9662. However, GP-75-mediated PPARγ upregulation was not affected by coincubation with the phosphatidylinositol 3-kinase inhibitor, LY294002. Collectively, GP-75 might be a novel PPARγ agonist that ameliorates cognitive deficit by enhancing brain glucose uptake via the activation of Akt/GLUT4 signaling in db/db mice.

Cadinane-Type Sesquiterpenoids with Cytotoxic Activity from the Infected Stems of the Semi-mangrove Hibiscus tiliaceus.

Eight new cadinane sesquiterpenoids (1-8), along with two known compounds (9 and 10), were isolated from infected stems of the semi-mangrove plant, Hibiscus tiliaceus. The structures of compounds 1-8 were elucidated through the analysis of their 1D and 2D NMR and MS data, and their absolute configurations were determined by comparing their experimental and calculated ECD spectra and by single-crystal X-ray diffraction. The two confused known compounds (9 and 10) were resolved using single-crystal X-ray crystallography. Compounds 1-3 have novel norsesquiterpene carbon skeletons arising from a ring contraction rearrangement. All obtained isolates were evaluated against the HepG2 and Huh7 cell lines, and compounds 1b, 2b, 4, 6, and 8 showed cytotoxic activity toward both cell lines, with IC50 values ranging from 3.5 to 6.8 µM.