Guaiane-type sesquiterpenoids with various ring skeletons from Daphne bholua uncovered by molecular networking and structural revisions of previously reported analogues.

The genus Daphne is a treasure-house of secondary metabolites with various biological effects, which inspired Daphne bholua being fully investigated phytochemically and biologically for the first time. Here, seven undescribed guaiane-type sesquiterpenoids (1-7) along with thirteen known analogues (8-20) were targeted and isolated from D. bholua using molecular networking. Their chemical structure and configurations were established via NMR spectroscopy analysis, NMR and ECD calculations, Snatzke's method, along with single-crystal X-ray diffraction technique. Moreover, two pairs of sesquiterpene isomers, either with prominent biological properties or with unprecedented skeleton, were revised by means of computer-assisted structure elucidation, chemical shift calculator using deep learning, etc. The inhibitory potentials of all isolates against acetylcholinesterase were evaluated in vitro and in silico.

Cytotoxic Guaianolide Sesquiterpenoids from Ainsliaea fragrans.

Twelve guaianolide-type sesquiterpene oligomers with diverse structures were isolated from the whole plants of Ainsliaea fragrans, including a novel trimer (1) and two new dimers (2, 3). The chemical structures of the new compounds were elucidated through spectroscopic data interpretation and computational calculations. Ainsfragolide (1) is an unusual guaianolide sesquiterpene trimer generated with a novel C-C linkage at C2'-C15″, which may be biosynthesized prospectively through a further Michael addition. Cytotoxicity results showed that ainsfragolide (1) was the most potent compound against five cancer cell lines with IC50 values in the range of 0.4-8.3 µM.

Dimeric guaianes from leaves of Xylopia vielana as snail inhibitors identified by high content screening.

The transcriptional repressor Snail trriggers epithelial-mesenchymal transition (EMT), the process allowing cancer cells with invasive and metastasis properties. In this study, we screened medicinal plants for the Snail inhibitory active components by high content screen (HCS) and found that the crude extract of Xylopia vielana leaves showed potential activity. Subsequently, bioassay-guided isolation of the extract of Xylopia vielana was performed to obtain twenty-four dimeric guaianes (1-24), including 16 new analogues (1-5, 8-11, 13-15, 17, 18, 21, and 22). Their structures were elucidated by the comprehensive application of multiple spectroscopic methods. Compounds 1, 11, 12, and 16 were initially identified as the active compounds. Wound healing assay, transwell migration assay and western blot experiments verified that compounds 1 and 12 inhibited the expression of Snail in a concentration-dependent manner, and compound 12 was verified as a potent tumor migration inhibitory agent. This work showed a practical strategy for the discovery of new Snail inhibitors from natural products and provided potential insights for dimeric guaianes as anticancer lead compounds specifically targeting Snail protein.

Artematrovirenins A-P, guaiane-type sesquiterpenoids with cytotoxicities against two hepatoma cell lines from Artemisia atrovirens.

Random screening revealed that the EtOH extract of Artemisia atrovirens showed significant cytotoxicity against two human hepatoma cell lines (HepG2 and Huh7) with the inhibitory ratio of 98.9% and 99.7% at the concentration of 100 µg/mL. Further bioactivity-guided isolation of active fraction led to 16 new guaiane-type sesquiterpenoids, artematrovirenins A-P (1-16). Their structures were elucidated by extensive spectroscopic data. The absolute stereochemistry of compounds 1 and 14 was determined by single-crystal X-ray diffraction analyses. Pharmacological evaluation suggested that five compounds (3, 5, 8, 10, and 15) exhibited cytotoxicity, compounds 3 and 5 displayed cytotoxicity against HepG2 cell line with an IC50 values of 8.0 and 16.0 µM, as well as against Huh7 cell line with values of 18.2 and 32.2 µM.

Liquid-Liquid Chromatography Separation of Guaiane-Type Sesquiterpene Lactones from Ferula penninervis Regel & Schmalh. and Evaluation of Their In Vitro Cytotoxic and Melanin Inhibitory Potential.

Ferula penninervis Regel & Schmalh. is a perennial plant used in Kazakh traditional folk medicine to treat epilepsy, neurosis, rheumatism, gastroduodenal ulcers, dyspepsia, wounds, abscesses or tumors. The aim of this work was to isolate series of sesquiterpene lactones from a crude methanolic root extract and investigate their in vitro cytotoxic potential against androgen-dependent prostate cancer LNCaP and epithelial prostate PNT2 cells, as well as to evaluate their melanin production inhibitory effects in murine melanoma B16F10 cells stimulated with α-melanocyte-stimulating hormone (αMSH). Two new (penninervin P and penninervin Q) and five known (olgin, laferin, olgoferin, oferin and daucoguainolactone F) guaiane-type sesquiterpene lactones were isolated with the use of a simple and fast liquid-liquid chromatography method. Olgin and laferin showed the most promising cytotoxic effects in LNCaP cells (IC50 of 31.03 and 23.26 µg/mL, respectively). Additionally, olgin, laferin, olgoferin, and oferin (10 µg/mL) potently impaired melanin release (40.67-65.48% of αMSH + cells) without influencing the viability of B16F10 cells. In summary, our findings might indicate that guaiane-type sesquiterpene lactones from F. penninervis could be regarded as promising candidates for further research in discovering new therapeutic agents with anti-prostate cancer and skin depigmentation properties.

Guaianolide Sesquiterpene Lactones from Centaurothamnus maximus.

Centaurothamnus maximus (family Asteraceae), is a leafy shrub indigenous to the southwestern Arabian Peninsula. With a paucity of phytochemical data on this species, we set out to chemically characterize the plant. From the aerial parts, two newly identified guaianolides were isolated: 3ß-hydroxy-4α(acetoxy)-4ß(hydroxymethyl)-8α-(4-hydroxy methacrylate)-1αH,5αH, 6αH-gual-10(14),11(13)-dien-6,12-olide (1) and 15-descarboxy picrolide A (2). Seven previously reported compounds were also isolated: 3ß, 4α, 8α-trihydroxy-4-(hydroxymethyl)-lαH, 5αH, 6ßH, 7αH-guai-10(14),11(13)-dien-6,12-olide (3), chlorohyssopifolin B (4), cynaropikrin (5), hydroxyjanerin (6), chlorojanerin (7), isorhamnetin (8), and quercetagetin-3,6-dimethyl ether-4'-O-ß-d-pyranoglucoside (9). Chemical structures were elucidated using spectroscopic techniques, including High Resolution Fast Atom Bombardment Mass Spectrometry (HR-FAB-MS), 1D NMR; 1H, 13C NMR, Distortionless Enhancement by Polarization Transfer (DEPT), and 2D NMR (1H-1H COSY, HMQC, HMBC) analyses. In addition, a biosynthetic pathway for compounds 1-9 is proposed. The chemotaxonomic significance of the reported sesquiterpenoids and flavonoids considering reports from other Centaurea species is examined.

Guaiane type of sesquiterpene with NO inhibitory activity from the root of Wikstroemia indica.

Roots of Wikstroemia indica is widely used in China as a folk medicine in treatment of many diseases. However, active compounds of guaiane type of sesquiterpene remain largely unknown. In the present work, five new guaiane of type sesquiterpene compounds wikstronone A-E, along with one known guaiane type of sesquiterpene compound were isolated from the petroleum and CH2Cl2 fraction of roots of Wikstroemia indica. Structures of these compounds including absolute configuration were determined by extensive NMR and CD spectroscopic analysis. The inhibitory activity of all isolated compounds were assayed against LPS-induced NO production in RAW 264.7 macrophages by Griess reagent. Among all compounds, wikstronone A (1) showed remarkable NO inhibitory activity comparable to that of positive control Indometacin. Wikstronone D and E (4 and 5) showed weak NO inhibitory activity. The isolated guaiane type of sesquiterpene may be potent NO synthetase inhibitors.

Monomeric and Dimeric Cytotoxic Guaianolide-Type Sesquiterpenoids from the Aerial Parts of Chrysanthemum indicum.

Twelve new guaianolide-type sesquiterpenoids (1-12) and five known guaianolide derivatives (13-17) were isolated from an aqueous ethanol extract of the aerial parts of Chrysanthemum indicum. Their structures were determined through spectroscopic data analysis. The absolute configurations of the new compounds were assigned by X-ray crystallography and electronic circular dichroism. Compound 5 shows multiple cytotoxic activities against four human naso-pharyngeal carcinoma (NPC) cell lines (CNE1, CNE2, SUNE-1, and HONE-1) and one human intestinal epithelial cell line (HT-29) with IC50 values of 4.6, 6.0, 3.5, 4.3, and 9.6 µM, respectively. Compound 16 exhibits weak cytotoxicity against four NPC cell lines, CNE1 (IC50 = 7.3 µM), CNE2 (IC50 = 7.4 µM), HONE-1 (IC50 = 7.6 µM), and SUNE-1 (IC50 = 5.6 µM), but no cytotoxicity against HT-29 (IC50 > 10 µM).

Vieloplains A-G, seven new guaiane-type sesquiterpenoid dimers from Xylopia vielana.

Seven new guaiane-type sesquiterpene dimers vieloplains A-G, connecting patterns through three different direct CC bonds compounds 1-5 (C-3 to C-3', C-4 to C-1'), compound 6 (C-2 to C-3', C-4 to C-2') and compound 7 (C-2 to C-1', C-4 to C-2') were isolated from the roots of Xylopia vielana. Their absolute configurations were established by NOESY analysis, the Cu Kα X-ray crystallographic the experiment circular dichroism (ECD) and the calculated ECD. Among them, only compound 6 showed a considerable cytotoxicity against DU145 cells with IC50 values of 9.5 µM. Flow cytometry analysis confirmed that 6 caused death of DU145 cells via apoptosis induction.

Guaianolides from Ormenis mixta: Structural Insights and Evaluation of Their Anti-inflammatory Profile.

In this paper, the isolation of five new guaianolides (1:  - 5: ) and four (6:  - 9: ) known sesquiterpenes from Ormenis mixta aerial parts is reported. The structural determination of the guaianolides was obtained by NMR spectroscopic data, as well as MS experiments. Their relative configurations were assigned by a combined quantum mechanical/NMR approach, comparing the experimental 13C/1H NMR chemical shift data and 1 J H-H homonuclear coupling constants with the related predicted values. The isolates were assayed for their anti-inflammatory potential evaluating nitric oxide release and cyclooxygenase-2 expression in J774A.1 macrophages treated with lipopolysaccharide from Escherichia coli. Our results indicated that, among the tested compounds, 1:  - 3: , and 7: were able to inhibit nitric oxide release, while all were able to inhibit cyclooxygenase-2 expression with different potencies.

Absolute Configurations and Bioactivities of Guaiane-Type Sesquiterpenoids Isolated from Pogostemon cablin.

Seven novel guaiane sesquiterpenoids (1-7) and three known seco-guaianes were isolated from the volatile oil of Pogostemon cablin. Their structures including absolute configurations were determined by spectroscopic analyses, a modified Mosher's method, and X-ray diffraction and ECD data. The results indicated that the ECD Cotton effects arising from one or two nonconjugated olefinic chromophores could be applied to define the absolute configurations of guaiane sesquiterpenoids. Compounds 3 and 6 exhibited significant vasorelaxant activity against phenylephrine-induced and KCl-induced contractions of rat aorta rings [half-maximal effective concentration (EC50) of 3 against PHE-induced contraction, 5.4 µM; EC50 of 6 against PHE- and KCl-induced contractions, 1.6 and 24.2 µM, respectively]. They also showed antifungal activity against Candida albicans (minimum inhibitory concentrations, 500 and 300 µM, respectively). In addition, 2 and 7-9 displayed a neuroprotective effect against glutamate-induced injury in PC12 cells.

Antiinflammation constituents from Curcuma zedoaroides.

Curcuma zedoaroides, a Zingiberaceae species, has been used for snake bite antidote and wound care in Thailand. Seven compounds were isolated from the bioactive chloroform extract consisted of one new guaiane sesquiterpene lactone, 5-epiphaeocaulisin A (4) and one new diarylheptanoid, 1,2,3,5-tetrahydroxy-1-(4-hydroxy-3-methoxyphenyl)-7-(4-hydroxyphenyl) heptane (7), together with five known guaiane-type sesquiterpene lactones including gweicurculactone (1), zedoalactone B (2), phaeocaulisin C (3), zedoalactone H (5), and zedoalactone E (6). The antiinflammation was investigated on NO and TNF-α production using RAW264.7 cells. In addition, the expressions of genes involved in inflammation including iNOS, COX-2, and TNF-α were assessed. The results found that Compounds 1-7 presented their antiinflammation against NO production. The most potential effects were demonstrated on Compounds 1 and 7 with IC50 of 27.3 and 32.6 µM, respectively. Although, Compounds 1 and 7 did not inhibit TNF-α production, their suppression on iNOS and COX-2 mRNA expression were revealed. These results support the ability of chloroform fraction, Compounds 1 and 7 on antiinflammation, whereas others exhibited moderate and mild effect.

New cytotoxic sesquiterpene lactones from Achillea cretica L. growing in Tunisia.

The phytochemical study of Achillea cretica growing in Tunisia led to the isolation of two novel sesquiterpene lactones, which have been designated achicretin 1 and achicretin 2. Their chemical structures were further confirmed by mass spectroscopy (ESI-MS) and by extensive application of one- and two-dimensional NMR spectroscopy. The isolated compounds were tested for their cytotoxic activity against four human cancer cell lines, IGROV-1, OVCAR-3, MCF-7, and HCT-116 using the MTT assay. It has been found that achicretin 2 exhibited more potent inhibitory activity with IC50 = values of 14.0 ± 1.0 and 16.0 ± 2.0 µM against OVCAR-3 and HCT-116 cells, respectively.

Three new elemanolides from the seeds of Vernonia anthelmintica.

Three new elemanolides, named vernonilides D (1), E (2), and F (3), along with four known sesquiterpenoids, including two elemanolides (4, 5), a guaianolide (6), and a germacranolide (7) were isolated from the seeds of Vernonia anthelmintica. The structures of them were elucidated based on 1D and 2D NMR experiments and comparison with published data. Cytotoxicity of the compounds against four human tumor cell lines was assayed. 6 showed strongly inhibitory effect against HCT-15 and PC-3 cell lines with IC50 values of 0.56 and 0.69 µM, respectively. The new compounds showed moderate cytotoxicity against four cell lines with IC50 values ranging from 9.1 to 28.1 µM.

[Guaianolides from aerial parts of Artemisia myriantha].

This study was performed to investigate the guaianolides from the aerial parts of Artemisia myriantha. The chemical constituents were isolated by chromatographic columns over silica gel, Sephadex LH-20, and ODS, as well as Semi-prep HPLC methods, and their structures were identified by NMR and MS data. Ten compounds were isolated and identified as follows: artemyriantholide E (1), tanaphillin (2), 1ß, 10ß-epoxydehydroleucodin (3), 5-hydroxyleucodin (4), dehydrocostuslactone (5), 3-O-methyl-iso-secotanapartholide (6), roxbughianin A (7), dehydroleucodin (8), arglabin (9), and 8α-acetoxyarglabin (10). Compound 1 was a new compound, and compounds 2-7 were isolated from this plant for the first time. Compound 3 exhibited selective cytotoxicity against human liver cancer (Bel-7402) with IC50 value of 5.35 µmol·L⁻¹, and 6 against human gastric cancer (BGC-823) with IC50 value of 2.68 µmol·L⁻¹, respectively.

Phytochemicals with NO inhibitory effects and interactions with iNOS protein from Trigonostemon howii.

A phytochemical investigation to obtain new NO inhibitors led to the isolation of nine compounds including one new guaiane-type sesquiterpenoid (1) and two new cleistanthane diterpenoids (2 and 3) from the stems of Trigonostemon howii. Their structures were elucidated on the basis of extensive 1D and 2D NMR spectroscopic data analysis, and the absolute configurations of new compounds 1-3 were established via comparison of experimental and calculated electronic circular dichroism (ECD) spectra. Compounds 2 and 3 possess a rare 3,4-seco-cleistanthane diterpenoid skeleton. All of the compounds showed inhibitory effects on lipopolysaccharide-induced NO production in murine microglial BV-2 cells. The further molecular docking studies indicated the strong interactions between some bioactive compounds with the iNOS protein, which revealed the possible and potential mechanism of NO inhibition of bioactive compounds.

Guaiane-Type Sesquiterpenoids from Fissistigma oldhamii Inhibit the Proliferation of Synoviocytes.

Three guaiane-type sesquiterpenoids, dysodensiols G-I (1-3), together with five known sesquiterpenoids (4-8) were isolated from the stems of Fissistigma oldhamii (Hemsl.) Merr. Compound 1 represents the first example of an ene(6 → 5)-abeo-14-norguaiane sesquiterpenoid derived from natural products. Their structures were elucidated by a combination of 1D and 2D NMR and MS spectra. The absolute configuration of 2 was determined by an X-ray crystallographic analysis. The inhibitory effect of all compounds on the proliferation of primary synovial cells was evaluated. Compound 3 showed a potent inhibitory effect on the proliferation of synoviocytes with an IC50 value of 1.0 µM.

Guaiane-Type Sesquiterpenoids from Alismatis Rhizoma and Their Anti-inflammatory Activity.

Twelve guaiane-type sesquiterpenoids, including four new ones, 10-O-methyl-orientalol A (1), 10-O-ethyl-alismoxide (2), 3ß,4ß-expoxy-chrysothol (3), orientalol G (4), and a new norsesquiterpenoid, orientalol H (5), were isolated from Chinese Alismatis Rhizoma, the dried rhizome of Alisma orientale. The structures of new compounds were elucidated on the basis of spectroscopic data. Moreover, the inhibition of lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW264.7 cells of all compounds was tested.

Two new guaiane-type sesquiterpenoids from Valeriana hardwickii and their cytotoxicity.

Two new guaiane-type sesquiterpenoids, named 4α,5α-epoxy-8ß-hydroxy-1α-hydro-α-guaiene (1) and 4α,5α-epoxy-1-hydroxy-α-guaiene (2), were isolated from the whole plants of Valeriana hardwickii. Their structures were elucidated on the basis of spectroscopic analysis. Compounds 1 and 2 showed weak cytotoxicity against the lung adenocarcinoma (A549) and hepatoma (Bel7402) cell lines with IC50 values of 9.2 and 8.5 µM, respectively.

New sesquiterpene lactones, vernonilides A and B, from the seeds of Vernonia anthelmintica in Uyghur and their antiproliferative activities.

A new guaianolide sesquiterpene lactone, vernonilide A (1), and a new elemanolide sesquiterpene lactone, vernonilide B (2), were isolated from the seeds of Vernonia anthelmintica, together with three known elemanolide sesquiterpene lactones (3-5). The structures of the isolated compounds were elucidated on the basis of physicochemical evidences. Compounds 1, 3, and 4 showed strong antiproliferative activities against three human cancer cell lines (A549, HeLa, and MDA-MB-231), with IC50 values ranging from 0.10 to 1.00µM. In addition, 5 exhibited significant antiproliferative activities against HeLa and MDA-MB-231 cells, with IC50 values ranging from 1.90 to 2.20µM. The antiproliferative activities of the acetyl derivatives 6 and 7 prepared from 4 and 3, respectively, against the three cell lines were 4-10-fold weaker than the original activities.