Eremophilane and cadinane sesquiterpenoids from the fruits of Alpinia oxyphylla and their anti-inflammatory activities.

The fruits of Alpinia oxyphylla have been used for centuries in China as both edible resources and traditional Chinese medicine. In order to identify structurally interesting and bioactive constituents from the fruits of A. oxyphylla, bioassay-guided fractionation and purification of the crude extracts were performed, which led to the isolation of 38 sesquiterpenoids, including six previously undescribed eremophilane sesquiterpenoids (1-6), six new cadinane sesquiterpenoids (23-24, 26-29), and 26 known analogues (7-22, 25 and 31-38). The structures of these compounds were elucidated by comprehensive spectroscopic data analysis, single crystal X-ray diffraction, quantum chemistry calculations (13C-NMR and ECD), and Mo2(OAc)4 reaction. Several of the isolated compounds (8, 13, 17, 18, 30, 31 and 35) showed moderate to strong inhibition of the secretion of cytokines (NO, TNF-α and IL-6) in LPS-stimulated BV-2 cells. Furthermore, western blot, immunofluorescence, and real-time PCR assays indicated that 18 could down-regulate the mRNA levels of TNF-α, IL-6, COX-2, and iNOS and the protein expression of COX-2 and iNOS. Meanwhile, 18 was able to partially inhibit the phosphorylation of ERK1/2, JNK, and p38. Thus, the discovery of structurally diverse anti-inflammatory sesquiterpenoids from the fruits of A. oxyphylla in this study could benefit the further development and utilization of this plant.

Two new diterpenoids from the rhizomes of Zingiber officinale.

Two undescribed labdane diterpenoids (5S,8S,9R,10S,11E)-8,17-epoxy-13,14-dinorlabd-11-en-13-one (1) and (5S,9R,10S,12E)-17-hydroxy-labd-7,12-dien-15(16)-olide (2), together with seven known sesquiterpenoids (3-9) and two known monoterpenoids (10-11) were isolated from the dried rhizome of Zingiber officinale. Their structures were elucidated by detailed spectroscopic data (IR, UV, HR-ESI-MS, 1D and 2D NMR), X-ray crystallographic and ECD analysis. Moreover, all the 11 compounds were tested for α-glucosidase inhibitory effects and 9 was found to exhibit stronger inhibitory effects at IC50 = 4.8 µM against a positive control acarbose with IC50 = 414.6 µM.

Discovery of pentapeptide-inhibitor hits targeting FKBP51 by combining computational modeling and X-ray crystallography.

FKBP51 is well-known as a cochaperone of Hsp90 machinery and implicated in many human diseases including stress-related diseases, tau-mediated neurodegeneration and cancers, which makes FKBP51 an attractive drug target for the therapy of FKBP51-associated diseases. However, it has been reported that only nature product rapamycin, cyclosporine A, FK506 and its derivatives exhibit good binding affinities when bound to FKBP51 by now. Given the advantages of peptide-inhibitors, we designed and obtained 20 peptide-inhibitor hits through structure-based drug design. We further characterized the interaction modes of the peptide-inhibitor hits on the FK1 domain of FKBP51 by biochemical and structural biology methods. Structural analysis revealed that peptide-inhibitor hits form U-shaped conformations and occupy the FK506 binding pocket and share similar interaction modes with FK506. Using molecular dynamics simulations, we delved into the interaction dynamics and found that hits are anchored to the FK506 binding pocket in a quite stable conformation. Meanwhile, it was shown that interactions between FK1 and peptide-inhibitor hits are mainly attributed to the hydrogen bond networks comprising I87 and Y113 and FPF cores of peptide-inhibitors involved extensive hydrophobic interactions. We presumed that the peptide design strategy based on the small molecule structure probably shed new lights on the peptide-inhibitor discovery of other targets. The findings presented here could also serve as a structural basis and starting point facilitating the optimization and generation of FKBP51 peptide-inhibitors with better bio-activities.

A new nitrogen-containing iridoid glycoside from lonicera macranthoides.

A new nitrogen-containing iridoid glycoside, named (7 R,3'R)-lonijapospiroside A (1), together with thirteen known iridoid glycosides, were isolated from the flower buds of Lonicera macranthoides. The structures of these compounds were established on the basis of spectroscopic analyses. Among them, compounds 1-4 are four diastereoisomers, and their absolute configurations were accurately established by the NOE spectra as well as comparison of their experimental and calculated ECD spectra. The anti-inflammatory activities of all isolates were evaluated by measuring their inhibitory effects on NO, IL-6, and TNF-α production in LPS stimulated RAW 264.7 macrophages. Compound 14 exhibited anti-inflammatory activities by inhibiting IL-6 with an IC50 value of 54.70 µM, comparable to that of the positive control (hydrocortisone, IC50: 62.6 ± 1.7 µM).

Three new cycloart-7-ene triterpenoid glycosides from Cimicifuga dahurica and their anti-inflammatory effects.

Ten cycloart-7-ene triterpenoid glycosides, including three new compounds (1-3), were isolated from the roots of Cimicifuga dahurica. Their structures were elucidated on the basis of extensive spectroscopic analyses, chemical methods and comparison with literatures. In addition, the isolates were evaluated for their inhibitory effects on the production of NO, as well as the expressions of iNOS and COX-2 in LPS-stimulated RAW 264.7 macrophages. The results showed that compounds 3, 5, 6, 7 and 8 can reduce the release of NO in a dose-dependent manner. Mechanistically, Western blot analysis indicated that the NO inhibitory effects relied on down-regulating the expression of iNOS, and partially associated with lowering the expression of COX-2.

Diarylheptanoid analogues from the rhizomes of Zingiber officinale and their anti-tumour activity.

Eight previously undescribed diarylheptanoids (1-8), together with fifteen known analogues (9-23), were isolated from the rhizomes of Zingiber officinale. Their structures were unambiguously determined by comprehensive spectroscopic analyses and electronic circular dichroism (ECD) calculations. It is worth mentioning that 1-3 are the first reported structures of diaryl ether heptanoids in Z. officinale, whereas 15-17 were isolated from Zingiber for the first time. Furthermore, a gene enrichment analysis of the interacting targets indicated that diarylheptanoids were mainly associated with the anti-tumor activity by affecting DNA damage signaling pathway. The results showed that 6, 16-19 had remarkable inhibitory effects against five tumor cell lines (A549, HepG2, HeLa, MDA-MB-231, and HCT116) with IC50 values ranging from 6.69-33.46 µM, and showed down-regulating the expression of ATR (ataxia telangiectasia mutated and RAD3-related) and CHK1 (checkpoint kinase 1) levels in HCT116 and A549 cell lines. Our studies not only enrich the structural diversity of diarylheptanoids in nature, but also discover several natural compounds for anti-tumor agents.

Structurally diverse sesquiterpenoids from the aerial parts of Artemisia annua (Qinghao) and their striking systemically anti-inflammatory activities.

Thirteen new sesquiterpenoids, arteannoides F-R (1-13), along with 13 known analogues (14-26), were isolated from the dried aerial parts of Artemisia annua L. Their structures, including absolute configurations, were unambiguously determined by a combination of physical data analyses (HRESIMS, 1D and 2D NMR, and ECD) as well as the crystal structures of 1, 5, 6, 15, 19, and 23. Among the isolated compounds, 1 features an unusual 11-oxatricyclo[6.2.1.04,9]undecan-2-ene ring system, 5 possesses an uncommon 4,11-ether bridged tricyclic framework, whereas 6 is a new eudesmane-type sesquiterpenoid formed via rearrangement of its carbon backbone. The systemically anti-inflammatory activities of all isolates were evaluated by measuring their inhibitory effects on PGE2, NO, TNF-α, and IL-6 production in LPS-stimulated RAW 264.7 macrophages. Moreover, the structure activity relationships of some compounds are summarized, this study will provide new structural templates for discovering potential anti-inflammatory agents.

New phenylpropanoid allopyranosides from the rhizomes of Cimicifuga dahurica.

Five new phenylpropanoid allopyranosides (1-5), along with five known compounds (6-10) were isolated from the rhizomes of Cimicifuga dahurica. Their structures were established by means of spectroscopic analyses and chemical methods, as well as comparison with literatures. The anti-inflammatory activities of all isolates were evaluated. Compounds 6, 9 and 10 exhibited inhibitory effects on PGE2 production in LPS stimulated RAW 264.7 macrophages with IC50 values of 19.72, 6.33 and 39.90 µM, respectively.

Phenolic acids and their glycosides from the rhizomes of Cimicifuga dahurica.

Phytochemical study on rhizomes of Cimicifuga dahurica resulted in the isolation of nine new neolignan and phenylpropanoid glycosides, cimicifugasides A-E (1, 2, 7-9), cimicifugamides B-D (3-5), shomaside G (6) along with four known compounds (10-13). Their structures were identified by extensive spectroscopic analyses (1D-, 2D-NMR, MS, CD, IR, UV) and chemical methods. Their anti-inflammatory potentials were evaluated by measuring their effects on PGE2 production of LPS-stimulated RAW264.7 cells, and compounds 12 and 13 showed moderate anti-inflammatory activities.

Lonimacranaldes A-C, three iridoids with novel skeletons from Lonicera macranthoides.

Lonimacranaldes A and B (1 and 2), along with one biogenetically related intermediate, lonimacranalde C (3), were isolated from the flower buds of Lonicera macranthoides. Characterized by an iridoid structure and an additional C-6 unit with an aldehyde group, compounds 1 and 2 are the first examples of hybrid iridoids possessing an unexpected 6/5/6 fused tricyclic ring system, while compound 3 serves as an important precursor for their generation. The structures of lonimacranaldes A-C (1-3) were revealed by extensive spectroscopic and X-ray diffraction analyses. A plausible biogenetic pathway for them was proposed. Compound 3 showed anti-inflammatory activities by inhibiting the production of IL-6 on LPS-induced RAW 264.7 cells with an IC50 value of 6.33 µM.

Dimeric Cadinane Sesquiterpenoid Derivatives from Artemisia annua.

Arteannoide A (1), an unusual cadinane dimer featuring a rare fused 6,8-dioxabicyclo[3.2.l]octan-7-one ring system, arteannoides B and C (2 and 3), two novel heterodimers incorporating a rearranged cadinene sesquiterpenoid and a phenylpropanoid, together with two new rearranged cadinene sesquiterpenoids 4 and 5, were isolated from Artemisia annua L. Their structures were determined by a combination of NMR spectroscopy, electronic circular dichroism calculations, and X-ray diffraction analyses. Compounds 2 and 3 showed inhibition of nitric oxide production in lipopolysaccharide-induced RAW 264.7 mouse macrophage cell lines with IC50 values of 4.5 and 2.9 µM, respectively.