Two new jatrophane diterpenoids from Euphorbia helioscopia with activity towards autophagic flux.

Nine jatrophane diterpenoids were isolated from the whole plant Euphorbia helioscopia, including two new ones, helioscopnins A (1) and B (2). Comprehensive spectroscopic data analysis and ECD calculations elucidated their structures, including absolute configurations. All compounds were evaluated for bioactivity towards autophagic flux by flow cytometry using HM mCherry-GFP-LC3 cells. Compounds 1, 3, 4, 5, 8, and 9 significantly increased autophagic flux.

Munronin V with 7/7/6 tricarbocyclic framework from Munronia henryi harms inhibits tau pathology by activating autophagy.

Munronin V (1), isolated from Munronia henryi Harms, is the first example, to the best of our knowledge, of an unprecedented 7/7/6 tricarbocyclic framework featuring an unusual A,B-seco-limonoid ring. The structures of munronin V were established from extensive spectroscopic and electronic circular dichroism (ECD) analyses. The novel A,B-seco with two seven-membered lactones was formed as a result of Baeyer-Villiger oxidation. Compound 1 activated autophagy and inhibited Tau pathology as revealed by flow cytometric analyses, confocal imaging analysis and western blotting, and this effect was mediated by transcription factor EB (TFEB). These findings suggested that 1 might have potential as a compound for combating Alzheimer's disease.

Terpenoids from Euphorbia helioscopia and Their Cytotoxic Activities against H1975 Cells.

Three previously undescribed diterpenoids, helioscopnoids A-C, and eight known compounds were isolated from the whole plants of Euphorbia helioscopia. Their structures were established by extensive analysis of spectra and data comparison with previous literatures. Among them, compound 4 was identified as 24,24-dimethoxy-25,26,27-trinoreuphan-3ß-ol with revised configurations of C-13, C-14, and C-17 (13R*, 14R*, 17R*). Cytotoxicity assays revealed that all compounds exhibited varying levels of cytotoxicity against H1975 cells, with compound 9 displaying the most potent activity, as indicated by cell viability rates of 18.13 % and 20.76 % at concentrations of 20 µM and 5 µM, respectively. This study expands the understanding of E. helioscopia terpenoids' structural diversity and biological activities, contributing to the exploration of potential therapeutic applications.

Quassinoids from Twigs of Harrisonia perforata (Blanco) Merr and Their Anti-Parkinson's Disease Effect.

Six new C-20 and one new C-19 quassinoids, named perforalactones F-L (1-7), were isolated from twigs of Harrisonia perforata. Spectroscopic and X-ray crystallographic experiments were conducted to identify their structures. Through oxidative degradation of perforalactone B to perforaqussin A, the biogenetic process from C-25 quassinoid to C-20 via Baeyer-Villiger oxidation was proposed. Furthermore, the study evaluated the anti-Parkinson's disease potential of these C-20 quassinoids for the first time on 6-OHDA-induced PC12 cells and a Drosophila Parkinson's disease model of PINK1B9. Perforalactones G and I (2 and 4) showed a 10-15% increase in cell viability of the model cells at 50 µM, while compounds 2 and 4 (100 µM) significantly improved the climbing ability of PINK1B9 flies and increased the dopamine level in the brains and ATP content in the thoraces of the flies.

Diterpenoids with an unprecedented ring system from Euphorbia peplus and their activities in the lysosomal-autophagy pathway.

Three novel jatrophane diterpenes, cyclojatrophanes A-C (1-3), were isolated from the seeds of Euphorbia peplus. Compounds 1-3 featured an unprecedented 5/5/5/11 tetracyclic ring system incorporating ditetrahydropyran rings. Their structures including their absolute configurations were established by extensive spectroscopic analysis, X-ray crystallographic experiments and chemical transformations. In addition, these compounds could significantly activate the lysosomal-autophagy pathway.

Perforalactones D and E, two new C-20 quassinoids with potential activity to induce lysosomal biogenesis from the twigs of Harrisonia perforata (Blanco) Merr.

Two new quassinoids (1 and 2) were isolated from the twigs of Harrisonia perforata (Blanco) Merr. Perforalactone E (2) possesses an uncommon hexacyclic 1α,12α:5α,13α-dicyclo-9ßH-picrasane skeleton. Its structure was determined based on spectroscopic data and X-ray crystallography. Compounds 1 and 2 could significantly induce lysosomal biogenesis through transcriptional activation of lysosomal genes.

Macrocyclic diterpenoids from the seeds of Euphorbia peplus with potential activity in inducing lysosomal biogenesis.

The first phytochemical investigation of the seeds of Euphorbia peplus led to the isolation and characterization of five new (1-5), named euphopepluanones A-E, and five known diterpenoids (6-10). Their structures were established by extensive spectroscopic analysis and X-ray crystallographic experiments. Euphopepluanones A-E (1-3) feature a very rare 5/11/5-tricyclic skeleton, and euphopepluanones D-E (4-5) represent the first report of lathyrane type diterpenoids found in E. peplus. The new compounds 1-5 were assessed for their activities to induce lysosomal biogenesis through LysoTracker Red staining, in which compounds 1 and 3 could significantly induce lysosomal biogenesis. In addition, compounds 1 and 3 could promote the nuclear translocation of TFEB, a master transcriptional factor of lysosomal genes, indicating that compounds 1 and 3 induced lysosomal biogenesis through activation of TFEB.

Identification of Ingol and Rhamnofolane Diterpenoids from Euphorbia resinifera and Their Abilities to Induce Lysosomal Biosynthesis.

The phytochemical study of Euphorbia resinifera afforded 18 structurally diverse diterpenoids, including 14 new ingol-type diterpenoids, euphorblins A-N (1-14), a new rhamnofolane diterpenoid, euphorblin O (15), and three known analogues (16-18). The structures of these compounds were deduced using 2D NMR spectroscopy and NOE experiments. The structure of compound 1 was confirmed by single-crystal X-ray crystallography. The abilities of the compounds to enhance lysosomal biosynthesis were evaluated through LysoTracker Red staining. Among the 10 active compounds, compounds 2, 4, and 18 showed remarkable immunofluorescence strength, and their LysoTracker staining intensities were 155.9%, 143.5%, and 140.7%, respectively, greater than that of the control. A series of lysosomal genes were also found to be upregulated by these compounds, which further confirms their ability to induce lysosome biosynthesis and suggests that these diterpenoids have potential as lead compounds for the development of drugs for the treatment of lysosome-related diseases.

Myritonines A-C, Alkaloids from Myrioneuron tonkinensis Based on a Novel Hexacyclic Skeleton.

Myritonines A-C (1-3), three new alkaloids bearing an unprecedented heterohexacyclic skeleton, were isolated from Myrioneuron tonkinensis. Their structures were determined by a combination of spectroscopic data and single-crystal X-ray diffraction analysis. Compound 3 represents the first Myrioneuron alkaloid featuring a unique trans-decahydroquinoline motif and was also found to possess a rare cyano functionality. Compounds 1 and 2 showed inhibition against the hepatitis C virus in vitro.

Alkaloids with Different Carbon Units from Myrioneuron faberi.

Three new Myrioneuron alkaloids, myrifamines A-C (1-3), with unique skeletons were isolated from Myrioneuron faberi. The absolute configuration of 1 was confirmed by single-crystal X-ray diffraction analysis, and the stereochemistry of the other two alkaloids was determined using a combination of ROESY experiments and calculated and experimental electronic circular dichroism spectra. Myrifamine C (3) is the first example of a symmetric dimer among the Myrioneuron alkaloids. Known alkaloids myrionamide (4) and schoberine (5) were also isolated, and experimental NMR and X-ray diffraction data suggest their structural revision. Compound 2 showed significant inhibitory activity toward the hepatitis C virus in vitro, with a therapeutic index (CC50/EC50) greater than 108.7.

Bioactive Limonoid Constituents of Munronia henryi.

Fourteen new limonoids, munronins A-N (1-14), and eight known limonoids (15-22) were isolated from the whole plants of Munronia henryi. The structures of the new compounds were elucidated by 2D NMR spectroscopy and mass spectrometry, and the structure of 8 was confirmed by single-crystal X-ray diffraction analysis. Compound 1 represents the first limonoid found with a novel 7-oxabicyclo[2.2.1]heptane moiety produced by incorporating C-11 and C-14 via an oxygen atom. All compounds were evaluated for their anti-tobacco mosaic virus (TMV) activity and in vitro cytotoxicity against the human cancer HL-60, SMMC-7721, A-549, MCF-7, and SW-480 cell lines. Among them, compounds 2, 8, 9, 10, 11, 12, 18, and 20 showed significant anti-TMV activity, with IC50 values in the range 19.6-44.4 µg/mL. Compounds 1 and 18 exhibited cytotoxic effects for all five cancer cell lines, with IC50 values between 0.4 and 4.8 µM.

Seven New Tetrahydroanthraquinones from the Root of Prismatomeris connata and Their Cytotoxicity against Lung Tumor Cell Growth.

The root of Prismatomeris connata has been used in China for centuries as the medicinal herb "Huang Gen" (HG), but its phytochemicals or active ingredients are not well understood. In this study, we performed chemical analysis of the ethyl acetate fraction of a HG ethanol extract. We thus isolated seven new tetrahydroanthraquinones, prisconnatanones C-I (compounds 1-7) from the root of P. connata and identified their structures using spectroscopic analyses. Their absolute configurations were established by both modified Mosher's and Mo2OAc4 methods, and ORD techniques. Their cytotoxicity was tested in a panel of human lung tumor cells (H1229, HTB179, A549 and H520 cell lines). Prisconnatanone I (7) showed the highest activity, with an IC50 value ranging from 2.7 µM to 3.9 µM in the suppression of tumor cell growth, and the others with chelated phenolic hydroxyls exhibited relatively lower activity (IC50: 8-20 µM). In conclusion, these data suggest that some of the natural tetrahydroanthraquinones in HG are bioactive, and hydroxylation at C-1 significantly increases the cytotoxicity of these compounds against lung tumor cell growth.

Unprecedented Quassinoids with Promising Biological Activity from Harrisonia perforata.

Perforalactone A (1), a new 20S quassinoid with a unique cagelike 2,4-dioxaadamantane ring system and a migrated side chain, was isolated from the plant Harrisonia perforata together with two biosynthetically related new quassinoids. The structures of these natural products were elucidated by NMR spectroscopy, X-ray diffraction analysis, computational modeling, and the CD excitation chirality method. The compounds exhibited notable biological properties, including insecticidal activity against Aphis medicaginis Koch and antagonist activity at the nicotinic acetylcholine receptor of Drosophila melanogaster. The structural features of these compounds may be related to their promising biological characteristics. Their biosynthesis and an alternative origin of quassinoid-type natural products are also discussed.

Cyclohexane-fused octahydroquinolizine alkaloids from Myrioneuron faberi with activity against hepatitis C virus.

Investigation of the alkaloids from Myrioneuron faberi, a plant unique to China, gave four pairs of enantiomers (1-4). (±)-ß-Myrifabral A (1) and (±)-α-myrifabral A (2) formed an inseparable mixture of anomers (cluster A), as did (±)-ß-myrifabral B (3) and (±)-α-myrifabral B (4) (cluster B). Their structures were determined by X-ray diffraction and NMR analysis. Compounds 1-4 possessed novel cyclohexane-fused octahydroquinolizine skeletons and represent the first quinolizidine alkaloids from the genus Myrioneuron. The epimers of cluster A (1 and 2) were modified and separated. In vitro, clusters A and B and their derivatives inhibited replication of hepatitis C virus (HCV, IC50 0.9 to 4.7 µM) with cytotoxicity lower than that of telaprevir.

Angustifonines A and B, cytotoxic bisindole alkaloids from Bousigonia angustifolia.

Two new bisindole alkaloids, angustifonines A (1) and B (2), comprising the union of a rearranged monoterpenoid quinoline and an aspidospermine alkaloid, as well as 27 known indole alkaloids were isolated from the twigs and leaves of Bousigonia angustifolia. Their structures and absolute configurations were elucidated by a combination of MS, NMR, and computational methods. Angustifonines A and B exhibited cytotoxicity against various human cancer cell lines with IC50 values of 2.71-16.22 µM. A possible biosynthesis pathway toward the new bisindole alkaloids 1 and 2 is presented.

Limonoids from Aphanamixis polystachya and their antifeedant activity.

Eight new aphanamixoid-type aphanamixoids (C-J, 1-8) and six new prieurianin-type limonoids, aphanamixoids K-P (9-14), along with 10 known terpenoids were isolated from Aphanamixis polystachya, and their structures were established by spectroscopic data analysis. Among the new limonoids, 13 compounds exhibited antifeedant activity against the generalist Helicoverpa armigera, a plant-feeding insect, at various concentration levels. In particular, compounds 1, 4, and 5 showed potent activities with EC50 values of 0.017, 0.008, and 0.012 µmol/cm(2), respectively. On the basis of a preliminary structure-activity relationship analysis, some potential active sites in the aphanamixoid-type limonoid molecules are proposed.

Antimicrobial Constituents of the Mature Carpels of Manglietiastrum sinicum.

Seven new compounds, including a eupodienone-type lignan (1), a dibenzocyclooctadiene-type lignan (2), three tetrahydrofuran-type lignans (3-5), and two 1-phenylbutyl benzoates (6, 7), together with six known compounds, were isolated from the mature carpels of Manglietiastrum sinicum. The structures of new compounds 1-7 were defined by spectroscopic techniques, and the absolute configuration of manglisin A (1) was determined by X-ray crystallography. Compounds 1-4 exhibited moderate antimicrobial activities (MIC values: 0.016-0.14 µM) against Staphylococcus aureus, MRSA 82(#), MRSA 92(#), MRSA 98(#), and MRSA 331(#). Compounds 2 and 3 showed weak cytotoxic activity against five human tumor cell lines.

Phragmalin limonoids from the stem barks of Chukrasia tabularis var. velutina.

Seven new phragmalin limonoids, chukvelutilides I-O (1-7), were isolated from the stem barks of Chukrasia tabularis var. velutina. Their structures were elucidated by extensive spectroscopic analysis. Among them, compound 1 showed moderate lethal activity against brine shrimp larvae, with an LC50 value of 84.1 µM.

New hippolide derivatives with protein tyrosine phosphatase 1B inhibitory activity from the marine sponge Hippospongia lachne.

Five new sesterterpenoids, compounds 1-5, have been isolated from the sponge Hippospongia lachne off Yongxing Island in the South China Sea. The structures of compounds 1-5 were elucidated through extensive spectroscopic analysis, including HRMS, 1D, and 2D NMR experiments. The stereochemistry, including absolute configurations of these compounds, was determined by spectroscopic, chemical, and computational methods. Compounds 1 and 5 showed moderate protein tyrosine phosphatase 1B (PTP1B) inhibitory activities with IC50 values of 5.2 µM and 8.7 µM, respectively, more potent than previously reported hippolides.

Design, Synthesis, Anti-TMV Activity, and Structure-Activity Relationships of Seco-pregnane C21 Steroids and Their Derivatives.

seco-pregnane C21 steroids exhibit high antiviral activity against the tobacco mosaic virus (TMV). However, the structural modification of seco-pregnane C21 steroids and the structure-activity relationship (SAR) of the modified compounds remain unevaluated. Hence, the present study investigated how variations in the original skeletons of natural seco-pregnane C21 steroids affect their antiviral activity. A series of glaucogenin C and A derivatives were designed and synthesized for the first time, and their anti-TMV activity was evaluated. Bioassay results showed that most of the newly designed derivatives exhibited good to excellent antiviral activity; among these derivatives, 5g, 5j, and 5l with higher antiviral activity than that of ningnanmycin emerged as new antiviral candidates. Reverse transcription-polymerase chain reaction and Western blotting assay revealed reduced levels of TMV coat protein (TMV-CP) gene transcription and TMV-CP protein expression, which confirmed the antiviral activity of these derivatives. These compounds also downregulated the expression of NtHsp70-1 and NtHsp70-061. Computational simulations indicated that 5l displayed strong van der Waals energy and electrostatic with the TMV coat protein, affording a lower binding energy (ΔGbind = -56.2 kcal/mol) compared with Ribavirin (ΔGbind = -47.6 kcal/mol). The SAR of these compounds was also evaluated, which demonstrated for the first time that substitutions at C-3 and double bonds of C-5/C-6 and C-13/C-18 are crucial for maintaining high anti-TMV activity.