Transient Receptor Potential Melastatin 7 (TRPM7) Ion Channel Inhibitors: Preliminary SAR and Conformational Studies of Xenicane Diterpenoids from the Hawaiian Soft Coral Sarcothelia edmondsoni.

Waixenicin A, a xenicane diterpene from the octocoral Sarcothelia edmondsoni, is a selective, potent inhibitor of the TRPM7 ion channel. To study the structure-activity relationship (SAR) of waixenicin A, we isolated and assayed related diterpenes from S. edmondsoni. In addition to known waixenicins A (1) and B (2), we purified six xenicane diterpenes, 7S,8S-epoxywaixenicins A (3) and B (4), 12-deacetylwaixenicin A (5), waixenicin E (6), waixenicin F (7), and 20-acetoxyxeniafaraunol B (8). We elucidated the structures of 3-8 by NMR and MS analyses. Compounds 1, 2, 3, 4, and 6 inhibited TRPM7 activity in a cell-based assay, while 5, 7, and 8 were inactive. A preliminary SAR emerged showing that alterations to the nine-membered ring of 1 did not reduce activity, while the 12-acetoxy group, in combination with the dihydropyran, appears to be necessary for TRPM7 inhibition. The bioactive compounds are proposed to be latent electrophiles by formation of a conjugated oxocarbenium ion intermediate. Whole-cell patch-clamp experiments demonstrated that waixenicin A inhibition is irreversible, consistent with a covalent inhibitor, and showed nanomolar potency for waixenicin B (2). Conformational analysis (DFT) of 1, 3, 7, and 8 revealed insights into the conformation of waixenicin A and congeners and provided information regarding the stabilization of the proposed pharmacophore.

Dauresorcinols A and B, two pairs of merosesquiterpenoid enantiomers with new carbon skeletons from Rhododendron dauricum.

Five pairs of new merosesquiterpenoid enantiomers, named dauresorcinols A-E (1-5), were isolated from the leaves of Rhododendron dauricum. Their structures were elucidated by comprehensive spectroscopic data analysis, quantum chemical calculations, Rh2(OCOCF3)4-induced ECD, and single-crystal X-ray diffraction analysis. Dauresorcinols A (1) and B (2) possess two new merosesquiterpene skeletons bearing an unprecedented 2,6,7,10,14-pentamethyl-11-oxatetracyclo[8.8.0.02,7.012,17]octadecane and a caged 15-isohexyl-1,5,15-trimethyl-2,10-dioxatetracyclo[7.4.1.111,14.03,8]pentadecane motif, respectively. Plausible biosynthetic pathways of 1-5 are proposed involving key oxa-electrocyclization and Wagner-Meerwein rearrangement reactions. (+)/(-)-1 and 3-5 showed potent α-glucosidase inhibitory activity, 3 to 22 times stronger than acarbose, an antidiabetic drug targeting α-glucosidase. Docking results provide a basis to design and develop merosesquiterpenoids as potent α-glycosidase inhibitors.

Discovery of highly functionalized grayanane diterpenoids from the flowers of Rhododendron molle as potent analgesics.

A systematical investigation on the chemical constituents of the flowers of Rhododendron molle (Ericaceae) led to the isolation and characterization of thirty-eight highly functionalized grayanane diterpenoids (1-38), including twelve novel analogues molleblossomins A-L (1-12). Their structures were elucidated by comprehensive methods, including 1D and 2D NMR analysis, calculated ECD, 13C NMR calculations with DP4+ probability analysis, and single crystal X-ray diffraction. Molleblossomins A (1), B (2), and E (5) are the first representatives of 2ß,3ß:9ß,10ß-diepoxygrayanane, 2,3-epoxygrayan-9(11)-ene, and 5,9-epoxygrayan-1(10),2(3)-diene diterpenoids, respectively. Molleblossomins G (7) and H (8) represent the first examples of 1,3-dioxolane-grayanane conjugates furnished with the acetaldehyde and 4-hydroxylbenzylidene acetal moieties, respectively. All grayanane diterpenoids 1-38 were screened for their analgesic activities in the acetic acid-induced writhing model, and all of them exhibited significant analgesic activities. Diterpenoids 6, 13, 14, 17, 20, and 25 showed more potent analgesic effects than morphine at a lower dose of 0.2 mg/kg, with the inhibition rates of 51.4%, 68.2%, 94.1%, 66.9%, 97.7%, and 60.0%, respectively. More importantly, even at the lowest dose of 0.04 mg/kg, rhodomollein X (14), rhodojaponin VI (20), and rhodojaponin VII (22) still significantly reduced the number of writhes in the acetic acid-induced pain model with the percentages of 61.7%, 85.8%, and 64.6%, respectively. The structure-activity relationship was summarized and might provide some hints to design novel analgesics based on the functionalized grayanane diterpenoids.

Rhodojaponin VI ameliorates podocyte injury related with MDM2/Notch1 pathway in rat experimental membranous nephropathy.

AIM: Rhodojaponin VI (R-VI) is the key compound of Rhododendron molle G. Don (Ericaceae) (RM) with effective clinical application in rheumatoid arthritis and chronic glomerulonephritis. In our study, we tried to explore the effect of R-VI on the rat model of membranous nephropathy. METHODS: The rat model of passive heymann nephritis (PHN) was established by injecting sheep anti-rat Fx1A serum at a single dose through the tail. The rats were orally administered R-VI (0.02 mg/kg) or FK506 (1 mg/kg) 1 day before PHN induction, which was kept for 4 weeks. Urine and blood samples as well as kidney tissue were collected for analysis. C5b-9-induced human podocyte cell (HPC) was employed for experiments in vitro. RESULTS: R-VI could alleviate glomerulonephritis progression and podocyte injury in PHN rats, as indicated by the decreased proteinuria and the elevated level of albumin, accompanied with reduced immune deposits, reversed podocyte injury in the kidneys. Furthermore, R-VI suppressed murine double minute 2 (MDM2) expression without the alteration in the protein level of p53 and decreased Notch1 expression independent of Numb regulation. Pre-treatment with R-VI in C5b-9-induced HPC blocked MDM2/Notch1 signalling pathway. CONCLUSION: Thus, R-VI ameliorates podocyte injury in rats with PHN, which was probably related with MDM2/Notch1 signalling pathway.

Divergent Synthetic Approach to Grayanane Diterpenoids.

The total syntheses of nine grayanane diterpenoids, namely, GTX-II (1), GTX-III (2), rhodojaponin III (3), GTX-XV (4), principinol D (5), iso-GTX-II (6), 1,5-seco-GTX-Δ1,10-ene (7), and leucothols B (8) and D (9), that belong to five distinct subtypes, were disclosed in a divergent manner. Among them, six members were accomplished for the first time. The concise synthetic approach features three key transformations: (1) an oxidative dearomatization-induced [5 + 2] cycloaddition/pinacol rearrangement cascade to assemble the bicyclo[3.2.1]octane carbon framework (CD rings); (2) a photosantonin rearrangement to build up the 5/7 bicycle (AB rings) of 1-epi-grayanoids; and (3) a Grob fragmentation/carbonyl-ene process to access four additional subtypes of grayanane skeletons. Density functional theory calculations were performed to elucidate the mechanistic origins of the crucial divergent transformation, which combined with late-stage synthetic findings provided insights into the biosynthetic relationships between these diverse skeletons.

Piericones A and B as Potent Antithrombotics: Nanomolar Noncompetitive Protein Disulfide Isomerase Inhibitors with an Unexpected Chemical Architecture.

Extracellular protein disulfide isomerase (PDI) is a promising target for thrombotic-related diseases. Four potent PDI inhibitors with unprecedented chemical architectures, piericones A-D (1-4), were isolated from Pieris japonica. Their structures were elucidated by spectroscopic data analysis, chemical methods, quantum 13C nuclear magnetic resonance DP4+ and electronic circular dichroism calculations, and single-crystal X-ray diffraction analysis. Piericones A (1) and B (2) were nanomolar noncompetitive PDI inhibitors possessing an unprecedented 3,6,10,15-tetraoxatetracyclo[7.6.0.04,9.01,12]pentadecane motif with nine contiguous stereogenic centers. Their biosynthetic pathways were proposed to include a key intermolecular aldol reaction and an intramolecular 1,2-migration reaction. Piericone A (1) significantly inhibited in vitro platelet aggregation and fibrin formation and in vivo thrombus formation via the inhibition of extracellular PDI without increasing the bleeding risk. The molecular docking and dynamics simulation of 1 and 2 provided a novel structure basis to develop PDI inhibitors as potent antithrombotics.

Highly oxygenated grayanane diterpenoids with structural diversity from the flowers of Rhododendron dauricum and their analgesic activities.

Twenty-eight grayanane diterpenoids (1-28) including 13 new ones, named daublossomins A-M (1-13), and two new natural products, 3-O-acetylgrayanotoxin II (14) and 10-epi-grayanotoxin III (15), were isolated from the flowers of Rhododendron dauricum L. (Ericaceae). Their structures were elucidated by means of comprehensive spectroscopic methods and quantum chemical calculations (13C NMR-DP4+ analysis and calculated ECD), and the absolute configurations of ten grayanane diterpenoids 1, 4, 5, 7, 8, 22, 23, 25, 27, and 28 were determined by X-ray crystallographic analysis. Daublossomin A (1) represents the first example of an 11,16-epoxygrayan-6-one diterpenoid. Daublossomins B (2) and C (3) are the first examples of 9ß,10ß-epoxygrayanane diterpenoids, and daublossomin I (9) is the second conjugated grayan-1(5),6(7),9(10)-triene diterpenoid. Compounds 1-11 and 13-27 were evaluated for their analgesic activities in the HOAc-induced writhing test in mice, and 1-8, 10, 11, 13, 15, 17, 18, 22-24, and 26 exhibited significant analgesic effects at a dose of 5.0 mg/kg (inhibition rates > 50%). Among them, daublossomins A (1) and F (6) still showed potent analgesic activity even at a lower dose of 0.2 mg/kg with the inhibition rates of 54.4% and 55.2%, respectively. Grayanotoxin III (20) showed more potent analgesic activities than the positive control, morphine, at a dose of 0.04 mg/kg. A preliminary structure-activity relationship for the analgesic grayanane diterpenoids was discussed, providing some useful clues to design and develop structurally novel potent analgesics.

A new megastimane sesquiterpenoid from the leaves of Cinnamomum cassia.

A new megastimane sesquiterpenoid, cassianol A (1), and five known analogues (2-6) were isolated from the leaves extract of Cinnamomum cassia. Their structures were elucidated by extensive spectroscopic methods and single-crystal X-ray diffraction analyses. All the isolates were isolated from C. cassia for the first time. The anti-inflammatory activities of compounds 1-6 were evaluated against nitric oxide (NO) production in LPS-induced RAW 264.7 mouse macrophages.

Anti-thrombotic effects mediated by dihydromyricetin involve both platelet inhibition and endothelial protection.

Classical antithrombotics and antiplatelets are associated with high frequencies of bleeding complications or treatment failure when used as single agents. The platelet-independent fibrin generation by activated endothelium highlights the importance of vascular protection in addition to platelet inhibition in thrombosis prevention. Dihydromyricetin (DHM), the most abundant flavonoid in Ampelopsis grossedentata, has unique vasoprotective effects. This study aims to characterize the antithrombotic potential of DHM. The effects of DHM on the activation of platelets and endothelial cells were evaluated in vitro. Calcium mobilization and activation of mitogen-activated protein kinases (MAPKs) were examined as the potential targets of DHM based on molecular docking analysis. The in vivo effects of DHM were determined in FeCl3-injured carotid arteries and laser-injured cremasteric arterioles. The results showed that DHM suppressed a range of platelet responses including aggregation, secretion, adhesion, spreading and integrin activation, and inhibited exocytosis, phosphatidylserine exposure and tissue factor expression in activated endothelial cells. Mechanistically, DHM attenuated thrombin-induced calcium mobilization and phosphorylation of ERK1/2 and p38 both in platelets and endothelial cells. Intravenous treatment with DHM delayed FeCl3-induced carotid arterial thrombosis. Furthermore, DHM treatment inhibited both platelet accumulation and fibrin generation in the presence or absence of eptifibatide in the laser injury-induced thrombosis model, without prolonging ex vivo plasma coagulation or tail bleeding time. DHM represents a novel antithrombotic agent whose effects involve both inhibition of platelet activation and reduction of fibrin generation as a result of endothelial protection.

Gelstriamine A, a Triamino Monoterpene Indole Alkaloid with a Caged 6/5/7/6/6/5 Scaffold and Analgesic Alkaloids from Gelsemium elegans Stems.

A novel triamino monoterpene indole alkaloid with an unprecedented skeleton, gelstriamine A (1), four new monoterpene indole alkaloids (2-5), and 12 known analogues (6-17) were isolated from Gelsemium elegans. The structures of 1-5 were established using extensive spectroscopic techniques, NMR calculations with iJ/dJ-DP4 and 2D C-H COSY ANNs analysis, ECD calculations, chemical methods, and single crystal X-ray diffraction analysis. Gelstriamine A (1) possesses an unprecedented 6/5/7/6/6/5 heterohexacyclic scaffold bearing a unique hexahydrooxazolo[4,5-b]pyridin-2(3H)-one motif, and a plausible biosynthetic pathway was proposed. All the isolated alkaloids 1-17 showed discernible analgesic activities in an acetic acid-induced writhing test in mice, and N-desmethoxyhumantenine N4-oxide (3) exhibited more potent analgesic activities than those of morphine at doses of 0.04 and 0.2 mg/kg.

Structurally Diverse Diterpenoids from the Roots of Salvia deserta Based on Nine Different Skeletal Types.

Twenty-four diterpenoids (1-24), classified into nine diverse carbon skeletal types, 8-nor-7(8→14),9(8→7)-di-abeo-abietane (1, 2, and 13), 7(8→14),9(8→7)-di-abeo-abietane (3 and 4), 6-nor-6,7-seco-abietane (5 and 6), 6,7-seco-abietane (7 and 11), 9,10-seco-abietane (8), abietane (9, 10, and 14-21), 11(9→8),20(10→11)-di-abeo-abietane (12), 15(13→12)-abeo-abietane (22 and 23), and 4,5-seco-20(10→5)-abeo-abietane (24), respectively, were isolated from the roots of Salvia deserta. The structures of 10 new diterpenoids, named salviadesertins A-J (1-10), were elucidated by spectroscopic data interpretation, quantum-chemical calculations including calculated 13C NMR-DP4+ analysis and electronic circular dichroism as well as X-ray crystallography analysis. The absolute configurations of compounds 1-3, 7, 14, and 22 were defined by single-crystal X-ray diffraction analysis. All the isolated diterpenoids 1-24 were evaluated for their cytotoxicity against five cancer cell lines, and 6-hydroxysalvinolone (14) showed micromolar potencies against MCF-7, A-549, SMMC-7721, and HL-60 cells, whereas the other diterpenoids were inactive (half-maximal inhibitory concentration greater than 10.0 µM).

Structurally diverse diterpenoids with eight carbon skeletons from Rhododendron micranthum and their antinociceptive effects.

Seventeen diterpenoids (1-17), classified into eight diverse carbon skeleton types, grayanane (1, 2, and 12), micranthane (3, 4, and 13), mollane (5-7 and 14), 1,5-seco-grayanane (8), kalmane (9-11), 1,5-seco-kalmane (15), A-homo-B-nor-ent-kaurane (16), and leucothane (17), respectively, were isolated from the leaves extract of Rhododendron micranthum. Among them, diterpenoids 1-9 are new compounds and their structures were elucidated via extensive spectroscopic methods, quantum chemical calculations including the 13C NMR-DP4+ analysis and electronic circular dichroism (ECD) calculations, and the single-crystal X-ray diffraction analysis. Micranthanol A (1) represents the first example of a 5αH,9αH-grayanane diterpenoid and a 6-hydroxy-6,10-epoxygrayanane diterpenoid, and micranthanone B (3) is the first 6,10-epoxymicranthane and the 5α-hydroxy-micranthane diterpenoids. 14-epi-Mollanol A (5) and mollanol B (6) represent the first examples of 14ß-hydroxymollane diterpenoids. It is the first time to report mollane, 1,5-seco-kalmane, and A-homo-B-nor-ent-kaurane type diterpenoids from Rhododendron micranthum. All the seventeen diterpenoids showed significant antinociceptive activities at a dose of 5.0 mg/kg, and it is the first time to evaluate the antinociceptive activity of 1,5-seco-kalmane diterpenoid. Among them, compounds 3, 11, 14, and 15 exhibited significant antinociceptive activities even at a lower dose of 1.0 mg/kg. A preliminary structure-activity relationship for the antinociceptive effects of diterpenoids 1-17 is discussed, which provided a new basis to develop novel potent analgesics.

Structurally diverse diterpenoids from Pieris japonica as potent analgesics.

Sixteen diterpenoids (1-16) including 10 new ones, pierisjaponins A-J (1-10), were isolated and identified from Pieris japonica, and their structures were classified into eight diverse carbon skeletons. Pierisjaponins A (1) and B (2) represent the first 1,5-seco-grayanane diterpenoid glucosides and only showed 17 carbon resonances instead of 26 carbons in the 13C NMR spectra, their structures were finally defined by single-crystal X-ray diffraction, and the unusual NMR phenomena were explained. Pierisjaponin E (5) is the first mollane diterpene glucoside. This is the first time to report ent-labdane (3, 4, and 11) and ent-rosane (15) type diterpenoids from the Ericaceae plants, which provided the precursors of the Ericaceae diterpenoids and enlarged the chemical diversity of Ericaceae diterpenoids. All the 16 isolates showed potent analgesic activities, and this is the first time to describe the analgesic activities of 1,5-seco-grayanane, ent-labdane, mollane, and ent-rosane type diterpenoids. A preliminary structure-activity relationship is discussed, which provided new clues to design novel analgesics based on the Ericaceae diterpenoids.

Lanostane triterpene glycosides from the flowers of Lyonia ovalifolia var. hebecarpa and their antiproliferative activities.

Sixteen lanostane-type triterpene glycosides including eight new ones, named lyonicarposides A-H (1-8), were isolated from the flowers of Lyonia ovalifolia var. hebecarpa (Franch. ex F.B. Forbes & Hemsl.) Chun (Ericaceae). The chemical structures of the new compounds were elucidated by the comprehensive spectroscopic techniques and chemical methods. The Mo2(OAc)4-induced electronic circular dichroism method was used to determine the absolute configurations of C-24 in lyonicarposides A (1), C (3), and E (5). This is the first phytochemical study on the flowers of L. ovalifolia var. hebecarpa. All the isolates were evaluated for their antiproliferative activities against SMMC-7721, HL-60, SW480, MCF-7, and A-549 cell lines. Lyonicarposides A (1) and B (2) showed moderate antiproliferative activities against five cancer cell lines with IC50 values ranging from 12.39 to 28.71 µM. Lyonicarposides C (3) and G (7) and lyonifoloside M (12) selectively inhibited the proliferation of HL-60 and MCF-7 cell lines with IC50 values ranging from 13.03 to 17.71 µM. Interestingly, lyonifoloside L (13) selectively inhibited the proliferation of MCF-7 cell line with an IC50 value of 16.27 µM. Their structure-activity-relationships were discussed.

Antiproliferative abietane quinone diterpenoids from the roots of Salvia deserta.

A total of twenty abietane quinone diterpenoids including ten new ones (1-10) were isolated from the roots extract of Salvia deserta. Their chemical structures were delineated by extensive spectrometric and spectroscopic techniques including HRESIMS, NMR, UV, IR, and single-crystal X-ray diffraction analysis, calculated 13C NMR-DP4+ analysis, calculated ECD, and Mo2(OAc)4-induced ECD. The absolute configurations of salvidesertone A (1), 8α,9α-epoxy-6-deoxycoleon U (18), and 7,20-epoxyroyleanone (19) were determined by single-crystal X-ray diffraction analysis. Salvidesertone A (1) represents the first example of a 9-hydroxyabieta-7(8)-ene quinone diterpenoid. This is the first report of the crystal structures of 8α,9α-epoxy-6-deoxycoleon U (18) and 7,20-epoxyroyleanone (19). Abietane quinone diterpenoids 1, 2, and 4-20 were evaluated for their antiproliferative activities against five cancer cell lines A-549, SMMC-7721, SW480, MCF-7, and HL-60 and a normal epithelial cell line BEAS-2B in vitro. Salvidesertones E (8) and F (9) selectively inhibited the proliferation of A-549, SMMC-7721, and SW480 cancer cell lines. Importantly, salvidesertones E (8) and F (9), horminone (13), taxoquinone (14), 7α-O-methylhorminone (15), and 8α,9α-epoxy-6-deoxycoleon U (18) showed more potent antiproliferative effects against A-549 than the positive control cis-platin. A preliminary structure-activity relationship for the antiproliferative effects of abietane quinone diterpenoids 1-20 was discussed.

Amaryllidaceae and Sceletium alkaloids.

Covering: July 2015 to June 2017. Previous review: Nat. Prod. Rep., 2016, 33, 1318-1343 Recent progress on the isolation, identification, biological activity and synthetic studies of the structurally diverse alkaloids from plants of family Amaryllidaceae has been summarized in this review. In addition, the structurally related alkaloids isolated from Sceletium species are discussed.

Grayanane Diterpenoids from the Leaves of Rhododendron auriculatum and Their Analgesic Activities.

Twenty-four grayanane diterpenoids (1-24) including 12 new ones (1-12) were isolated from Rhododendron auriculatum. The structures of the new grayanane diterpenoids (1-12) were defined via extensive spectroscopic data analysis. The absolute configurations of compounds 2-4, 10-12, 14, and 16 were established by single-crystal X-ray diffraction analysis, and electronic circular dichroism data were used to define the absolute configurations of auriculatols D (8) and E (9). Auriculatol A (1) is the first example of a 5,20-epoxygrayanane diterpenoid bearing a 7-oxabicyclo[4.2.1]nonane motif and a trans/cis/cis/cis-fused 5/5/7/6/5 pentacyclic ring system. Auriculatol B (2) is the first example of a 3α,5α-dihydroxy-1-ßH-grayanane diterpenoid. 19-Hydroxy-3-epi-auriculatol B (6) and auriculatol C (7) represent the first examples of 19-hydroxygrayanane and grayan-5(6)-ene diterpenoids, respectively. Diterpenoids 1-24 showed analgesic activities in the writhing test induced by HOAc, and 2, 6, 10, 13, 19, and 24 at a dose of 5.0 mg/kg exhibited significant analgesic effects (inhibition rates >50%). Grayanane diterpenoids grayanotoxins I (19) and IV (24) at doses of 0.2 and 0.04 mg/kg showed more potent analgesic activities than morphine.

Protein Tyrosine Phosphatase 1B Inhibitory Iridoids from Psydrax subcordata.

Phytochemical investigation of the leaves and bark of Psydrax subcordata has led to the isolation of six new iridoids, subcordatanols I-V (1-4 and 6) and 1-O-methylcrescentin I (5), along with two known analogues (7 and 8). Among them, subcordatanol I (1) is the first example of a 3,8-monoepoxy-iridoid featuring a caged 2-oxa-bicyclo[3.2.1]octane core. The absolute stereochemistry at C-4 of 3, 4, and 6 was established through their acid-catalyzed reaction products subcordatalactones A (3a), B (4a), and C (6a), respectively. Subcordatanols I (1) and II (2), as well as subcordatalactones A (3a) and B (4a), displayed inhibitory activity against protein tyrosine phosphatase 1B (PTP1B). Enzyme kinetic studies indicated that 3a and 4a are competitive inhibitors. A molecular docking study is also reported.

Antinociceptive Grayanane Diterpenoids from the Leaves of Pieris japonica.

Thirteen new grayanane diterpenoids (1-13) and 15 known analogues (14-28) were isolated from a leaf extract of Pieris japonica. Their structures were determined by spectrometric and spectroscopic methods, including HRESIMS, NMR, IR, and UV. The absolute configurations of 1, 3, 7-9, and 16 were defined by single-crystal X-ray diffraction analysis. 17-Hydroxygrayanotoxin XIX (1) represents the first example of a 17-hydroxygrayan-15(16)-ene diterpenoid. Diterpenoids 1-28 were evaluated for their antinociceptive activities, and 4, 9, 13, 21, and 26-28 displayed significant antinociceptive activities at a dose of 5.0 mg/kg (ip) in the HOAc-induced writhing test in mice. 17-Hydroxygrayanotoxin XIX (1) exhibited potent antinociceptive effects with writhe inhibition rates of 56.3% and 64.8% at doses of 0.04 and 0.2 mg/kg, respectively, which were almost equivalent to the positive control, morphine. Rhodomollein X (26) and rhodojaponin VI (27) showed more potent antinociceptive effects than morphine at doses of 0.04 and 0.2 mg/kg. A preliminary structure-activity relationship for the antinociceptive effects of diterpenoids 1-28 is discussed.

Grayanane Diterpenoid Glucosides from the Leaves of Rhododendron micranthum and Their Bioactivities Evaluation.

Thirteen new grayanane diterpenoid glucosides, 3- epi-grayanoside B (1), micranthanosides A-E (2-6), 7α-hydroxygrayanoside C (7), micranthanoside F (8), 14ß-acetyoxymicranthanoside F (9), micranthanoside G (10), 14- O-acetylmicranthanoside G (11), 14ß-hydroxypieroside A (12), and micranthanoside H (13), and six known analogues (14-19) were isolated from the leaves of Rhododendron micranthum. The structures of 1-19 were elucidated based on spectroscopic analysis, comparison with literature, and chemical methods. The absolute configurations of 3- epi-grayanoside B (1) and micranthanosides A (2) and C (4) were defined by single-crystal X-ray diffraction analysis. This is the first report of the crystal structures of grayanane diterpenoid glucosides. 3- epi-Grayanoside B (1) represents the first example of a 3α-oxygrayanane diterpenoid glucoside, and micranthanosides A-D (2-5) are the first examples of 5α-hydroxy-1-ß H-grayanane diterpenoids. In addition, micranthanosides C-F (4-6 and 8) and 14ß-acetyoxymicranthanoside F (9) represent the first examples of grayanane glucosides with the glucosylation at C-16. All the grayanane diterpenoid glucosides 1-19 were assayed for their anti-inflammatory, antitumor, and PTP1B inhibitory activities, but did not show significant activities at 40 µM. Grayanane diterpenoid glucosides 1-18 were evaluated for their antinociceptive activity, and compounds 2, 3, 7-10, 12, 13, and 16 showed significant antinociceptive effects with percentage inhibitions in excess of 50%.