Publications by authors named "Wei-Lie Xiao"

143 Publications

Leojaponin inhibits NLRP3 inflammasome activation through restoration of autophagy via upregulating RAPTOR phosphorylation.

J Ethnopharmacol 2021 Oct 9;278:114322. Epub 2021 Jun 9.

Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Provincial Center for Research & Development of Natural Products, School of Chemical Science and Technology, Yunnan University, Kunming, 650091, China. Electronic address:

Ethnopharmacological Relevance: Duan Teng Yimu decoction is a Chinese herbal medicine compound with proven therapeutic effects on inflammasome-related diseases, such as rheumatoid arthritis. This decoction consists of three Chinese herbal medicines, including Leonurus japonicus (L. japonicus), which promotes the blood circulation and exhibits detumescence activity, traditionally curing gynecologic and inflammasome diseases.

Aim Of The Study: To explore the anti-inflammasome activity and the underlying mechanisms of action of the compounds from L. japonicus.

Materials And Methods: A series of compounds were isolated from L. japonicus. Their anti-inflammasome activities were evaluated in macrophages that were co-stimulated by lipopolysaccharide (LPS) and NLRP3 inflammasome inducers. NLRP3 inflammasome formation and apoptosis speck like containing a CARD (ASC) oligomerization were evaluated by immunofluorescent microscopy and Western blot analysis. The regulation of autophagy after treatment of this compound was also evaluated. Lastly, in vivo activity of Leojaponin was analyzed in a mouse acute gouty arthritis model.

Results: Here we show that Leojaponin, a diterpenoid compound from L. japonicus, suppressed lactate dehydrogenase and IL-1β release in Nigericin-stimulated macrophages in a pyroptosis model. Leojaponin inhibits NLRP3 inflammasome activation in both J774A.1 cells and bone marrow-derived macrophages in a dose dependent manner. Moreover, Leojaponin suppressed NLRP3-mediated ASC specks formation and ASC oligomerization. These activities of Leojaponin depend on restoration of autophagy via promoting RAPTOR phosphorylation. Furthermore, Leojaponin ameliorated monosodium urate (MSU)-induced acute gouty arthritis in vivo.

Conclusion: Our findings suggest that Leojaponin inhibits NLRP3 inflammasome activation through enhancing autophagy via RAPTOR phosphorylation, thereby highlighting Leojaponin as a potent drug for inflammasome-related diseases.
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http://dx.doi.org/10.1016/j.jep.2021.114322DOI Listing
October 2021

Synthesis of nigranoic acid and manwuweizic acid derivatives as HDAC inhibitors and anti-inflammatory agents.

Bioorg Chem 2021 Apr 16;109:104728. Epub 2021 Feb 16.

Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Research & Development Center for Natural Products, School of Chemical Science and Technology, Yunnan University, Kunming 650091, PR China. Electronic address:

As a successful anti-tumor drug target, the family of histone deacetylases (HDACs) is also a critical player in immune response, making the research of anti-inflammatory HDAC inhibitors an attractive new focus. In this report, triterpenoids nigranoic acid (NA) and manwuweizic acid (MA) were identified as HDAC inhibitors through docking-based virtual screening and enzymatic activity assay. A series of derivatives of NA and MA were synthesized and assessed for their biological effects. As a result, hydroxamic acid derivatives of NA and MA showed moderately increased activity for HDAC1/2/4/6 inhibition (the lowest IC against HDAC1 is 1.14 μM), with no activity against HDAC8. In J774A.1 macrophage, compound 1-3, 13 and 17-19 demonstrated inhibitory activity against lactate dehydrogenase (LDH) and IL-1β production, without affecting cell viability. Compound 19 increased the histone acetylation level in J774A.1 cells, as well as inhibited IL-1β maturation and caspase-1 cleavage. These results indicated that compound 19 blocks the activation of NLRP3 inflammasome, probably related to HDAC inhibition. This work provided a natural scaffold for developing low-cytotoxic and anti-inflammatory HDAC inhibitors, as well as a class of tool molecules for studying the relationship between HDACs and NLRP3 activation.
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http://dx.doi.org/10.1016/j.bioorg.2021.104728DOI Listing
April 2021

Toonaones A-I, limonoids with NLRP3 inflammasome inhibitory activity from Toona ciliata M. Roem.

Phytochemistry 2021 Apr 14;184:112661. Epub 2021 Jan 14.

Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming, Yunnan, 650091, China. Electronic address:

Nine undescribed limonoids, 18(13 → 14)-abeo-15β,21-dihydroxy-24,25,26,27-tetranor-3,7-dioxoapotirucalla-1,9(11),13(17),20(22)-tetraen-23,21-olide (Toonaone A), 21-hydroxy-24,25,26,27-tetranor-3,7,15-trioxoapotirucalla-1,9(11),20(22)-trien-23,21-olide (Toonaone B), 7α,21-dihydroxy-12α-isobutyryl-24,25,26,27-tetranor-3,15-dioxoapotirucalla-1,20(22)-dien-23,21-olide (Toonaone C), 7,8-seco-7-methyl ester-11β-acetoxy-14β,15β-epoxy-21-hydroxy-24,25,26,27-tetranor-3-oxoapotirucalla-1,8(30),20(22)-trien-23,21-olide (Toonaone D), 7,8-seco-7-methyl ester-11β-acetoxy-14β,15β-epoxy-23-hydroxy-24,25,26,27-tetranor-3-oxoapotirucalla-1,8(30),20(22)-trien-21,23-olide (Toonaone E), 7,8-seco-7-methyl ester-11β-acetoxy-14β,15β-epoxy-6β,21-dihydroxy-24,25,26,27-tetranor-3-oxoapotirucalla-1,8(30),20(22)-trien-23,21-olide (Toonaone F), 7,8-seco-7-methyl ester-14β,15β-epoxy-8α,21-dihydroxy-24,25,26,27-tetranor-3-oxoapotirucalla-1,20(22)-dien-23,21-olide (Toonaone G), 7,8-seco-7-methyl ester-14β,15β-epoxy-6β,8α,21-trihydroxy-24,25,26,27-tetranor-3-oxoapotirucalla-1,20(22)-dien-23,21-olide (Toonaone H), 7,8-seco-7-methyl ester-14β,15β-epoxy-6β,8α,21-trihydroxy-24,25,26,27-tetranor-3-oxoapotirucalla-1,20(22)-dien-21,23-diimide (Toonaone I), and five known analogues were isolated from the twigs of Toona ciliata M. Roem. (Meliaceae). Toonaone A possesses the first rare 18(13 → 14)-abeo-limonoid skeleton reported from the genus Toona. Their structures were elucidated using spectroscopic data analyses and quantum chemistry calculations. Biological evaluation showed that toonaone C, toonaone D, toonaone G, toonaciliatavarin F, and toonaciliatavarin G exhibited significant anti-NLRP3 inflammasome activity with IC values ranging from 3.74 to 18.7 μM. GMDMD, IL-1β, and caspase-1 analyses suggested that toonaone D inhibited NLRP3 inflammasome activation and blocked macrophage pyroptosis.
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http://dx.doi.org/10.1016/j.phytochem.2021.112661DOI Listing
April 2021

SWL-1 Reverses Fluconazole Resistance in by Regulating the Glycolytic Pathway.

Front Microbiol 2020 16;11:572608. Epub 2020 Oct 16.

Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming, China.

is a ubiquitous clinical fungal pathogen. Prolonged use of the first-line antifungal agent fluconazole (FLC) has intensified fungal resistance and limited its effectiveness for the treatment of fungal infections. The combined administration of drugs has been extensively studied and applied. SWL-1 is a lignin compound derived from the Traditional Chinese Medicine . In this study, we show that SWL-1 reverses resistance to fluconazole in when delivered in combination, with a sharp decrease in the IC of fluconazole from >200 to 3.74 ± 0.25 μg/ml, and also reverses the fluconazole resistance of , with IC from >200 to 5.3 ± 0.3 μg/ml. Moreover, killing kinetics curves confirmed the synergistic effects of fluconazole and SWL-1. Intriguingly, when SWL-1 was administered in combination with fluconazole in a mouse model of systemic infection, the mortality of mice was markedly decreased and fungal colonization of the kidney and lung was reduced. Further mechanistic studies showed that SWL-1 significantly decreased intracellular adenosine 5'-triphosphate (ATP) levels and inhibited the function of the efflux pump responsible for fluconazole resistance of . Proteomic analysis of the effects of SWL-1 on showed that several enzymes were downregulated in the glycolytic pathway. We speculate that SWL-1 significantly decreased intracellular ATP levels by hindering the glycolysis, and the function of the efflux pump responsible for fluconazole resistance of was inhibited, resulting in restoration of fluconazole sensitivity in FLC-resistant . This study clarified the effects and mechanism of SWL-1 on and , providing a novel approach to overcoming fungal resistance.
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http://dx.doi.org/10.3389/fmicb.2020.572608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596347PMC
October 2020

Diterpenoids from Callicarpa rubella and their in vitro anti-NLRP3 inflammasome activity.

Fitoterapia 2020 Nov 3;147:104774. Epub 2020 Nov 3.

Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Research & Development Center for Natural Products, School of Chemical Science and Technology, Yunnan University, Kunming 650091, People's Republic of China. Electronic address:

Nine new diterpenoids, Rubellacrns A - I (1-9), including five isopimaranes (1-4, 9), four pimaranes (5-8), together with five known isopimarane analogues (10-14), were isolated from Callicarpa rubella. The structures of these compounds were unambiguously established by HR-ESIMS and NMR spectroscopic data, the absolute configurations of compounds 5 and 9 were determined by ECD. All the isolated compounds were tested for their anti-inflammatory effects and compounds 2 and 11-14 showed NLRP3-inflammasome inhibitory activity with IC values ranging from 7.02 to 14.38 μM.
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http://dx.doi.org/10.1016/j.fitote.2020.104774DOI Listing
November 2020

Rubellawus A-D, Four New Diterpenoids Isolated from Callicarpa rubella and Their Anti-NLRP3 Inflammasome Effects.

Chem Biodivers 2020 Dec 26;17(12):e2000798. Epub 2020 Nov 26.

Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Research and Development Center for Natural Products, School of Chemical Science and Technology, Yunnan University, Kunming, 650091, P. R. China.

Four new diterpenoids, rubellawus A-D (1-4), along with three known compounds, were isolated and identified from the flowers of Callicarpa rubella. Their structures were elucidated by various spectroscopic analysis. All the compounds were screened for their anti-inflammatory activity and 14α-hydroxyisopimaric acid and isopimaric acid showed significant NLRP3 inflammasome inhibitory activity with IC values of 7.02 and 3.99 μM.
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http://dx.doi.org/10.1002/cbdv.202000798DOI Listing
December 2020

Toonaolides A-X, limonoids from Toona ciliata: Isolation, structural elucidation, and bioactivity against NLRP3 inflammasome.

Bioorg Chem 2020 12 10;105:104363. Epub 2020 Oct 10.

Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming, Yunnan 650091, People's Republic of China. Electronic address:

Twenty-four new limonoids, toonaolides A-X (1-24), characterized with an α,β-unsaturated-γ-lactone A-ring were isolated from the twigs of Toona ciliata. Their structures and absolute configurations were elucidated by spectroscopic data, X-ray diffraction crystallography, and quantum chemistry calculations. Most of the isolated compounds (except 9, 18, and 24 which possessed the maleimide ring) featured the rare 21-hydroxybutenolide or 23-hydroxybutenolide moieties. In particular, compound 1 has an unprecedented limonoid architecture with 6/6 cis-fused A/B ring system and 2 has an unusual tetrahydrofuran ring B skeleton, featuring a 7/5/6/5 ring system. The biological evaluation showed that compounds 9, 11, 12, 14, and 18 exhibited significantly anti-NLRP3 inflammasome activity with IC values ranging from 3.2 to 9.7 μM. Analysis of IL-1β and caspase-1 expression revealed that compounds 11 and 12 are selective inhibitors of NLRP3 inflammasome, which could ameliorate cell pyroptosis by blocking NLRP3 inflammasome activation.
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http://dx.doi.org/10.1016/j.bioorg.2020.104363DOI Listing
December 2020

Euphopias A-C: Three Rearranged Jatrophane Diterpenoids with Tricyclo[8.3.0.0]tridecane and Tetracyclo[11.3.0.0.0]hexadecane Cores from .

Org Lett 2020 10 29;22(20):7820-7824. Epub 2020 Sep 29.

Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; Yunnan Research & Development Center for Natural Products; School of Chemical Science and Technology, Yunnan University, Kunming 650091, P. R. China.

Euphopias A-C (-), three rearranged jatrophane-type diterpenoids with tricyclo[8.3.0.0]tridecane ( and ) and tetracyclo[11.3.0.0.0]hexadecane () cores, were isolated from . Comprehensive spectroscopic analyses, quantum-chemical calculations, and X-ray diffractions were used to identify their structures. Compounds - could significantly inhibit NLRP3 inflammasome activation and block NLRP3 inflammasome-induced pyroptosis. Additionally, a mechanistic study revealed that could ameliorate mitochondria damage, thereby interrupting NLRP3 inflammasome activation.
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http://dx.doi.org/10.1021/acs.orglett.0c02676DOI Listing
October 2020

Structurally Diverse Labdane Diterpenoids from and Their Anti-inflammatory Properties in LPS-Induced RAW264.7 Cells.

J Nat Prod 2020 09 16;83(9):2545-2558. Epub 2020 Sep 16.

Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; Yunnan Research & Development Center for Natural Products, School of Chemical Science and Technology, Yunnan University, Kunming, Yunnan 650091, People's Republic of China.

A phytochemical study on the aerial parts of led to the isolation and identification of 38 labdane diterpenoids, including 18 new (, , , , -, , -, , ) and 20 known (-, -, , , -, , ) analogues. Their structures were elucidated based on physical data analysis, including 1D and 2D NMR, HRMS, UV, IR, and X-ray diffraction. The structure of the known compound was confirmed by single-crystal X-ray diffraction data. These compounds can be divided into furanolabdane (-), tetrahydrofuranolabdane (-), lactonelabdane (-), labdane (-), and -labdane (-) type diterpenoids. All compounds were screened by lipopolysaccharide (LPS)-induced nitric acid (NO) production in RAW264.7 cells to evaluate anti-inflammatory effects. Compounds , , -, -, -, and inhibited NO production with IC values lower than 50 μM, with compound being the most active, with an IC value of 3.9 ± 1.7 μM. Further studies show that compound inhibits pro-inflammatory cytokine production and IKK α/β phosphorylation and restores the IκB expression levels in the NF-κB signaling pathway.
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http://dx.doi.org/10.1021/acs.jnatprod.9b00597DOI Listing
September 2020

Immunomodulatory and antitumour bioactive labdane diterpenoids from Leonurus japonicus.

J Pharm Pharmacol 2020 Nov 5;72(11):1657-1665. Epub 2020 Aug 5.

Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming, China.

Objectives: Two labdane diterpenoids, leojapone B and heteronone B, were isolated from Leonurus japonicus Houtt., and their biological activity were evaluated in this study.

Methods: Human and mouse cancer cells, human peripheral blood mononuclear cells (PBMCs) and mouse macrophages (RAW264.7 cells) were used to evaluate the activity of leojapone B and heteronone B, while the in vivo effects of leojapone B were further examined in Lewis Lung Cancer tumour-bearing mice.

Key Findings: In vitro studies showed that leojapone B selectively inhibited the proliferation of lung cancer cells, and both leojapone B and heteronone B inhibited the production of pro-inflammatory cytokines in activated PBMCs. In tumour-bearing mice model, lung tumours were reduced in size in mice treated with intraperitoneal injections of leojapone B at 20 and 30 mg/kg for 14 days. The population ratio of CD4 /CD8 T cells in mouse spleens was found to be increased, while regulatory T cells were decreased after leojapone B treatment.

Conclusions: The inhibitory effects of leojapone B in mouse lung tumours were demonstrated for the first time in this study. The immunomodulatory activity of heteronone B were also demonstrated. Our findings indicated that both leojapone B and heteronone B may act as active components in L. japonicus.
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http://dx.doi.org/10.1111/jphp.13348DOI Listing
November 2020

Design, synthesis and anti-HIV evaluation of 5-alkyl- 6-(benzo[d][1,3]dioxol-5-alkyl)-2-mercaptopyrimidin-4(3H)-ones as potent HIV-1 NNRTIs.

Bioorg Chem 2020 09 26;102:104041. Epub 2020 Jun 26.

Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming 650091, China. Electronic address:

In order to discover and develop the new HIV-1 NNRTIs, a series of 5-alkyl-6-(benzo[d][1,3]dioxol-5-ylalkyl)-2-mercaptopyrimidin-4(3H)-ones was synthesized and screened for their in vitro cytotoxicity against HIV-1. Most of the compounds we synthetized showed high activity against wild-type HIV-1 strain (IIIB) while IC values are in the range of 0.06-12.95 μM. Among them, the most active HIV-1 inhibitor was compound 6-(benzo[d][1,3]dioxol-5-ylmethyl)-5-ethyl-2-((2-(4-hydroxyphenyl)-2-oxoethyl)thio)pyrimidin-4(3H)-one (5b), which exhibited similar HIV-1 inhibitory potency (IC = 0.06 μM, CC = 96.23 μM) compared with nevirapine (IC = 0.04 μM, CC >200 μM) and most of compounds exhibited submicromolar IC values indicating they were specific RT inhibitors. The compounds 5b, 6-(benzo[d] [1,3]dioxol-5-yl)-5-ethyl-2-((2-(4-hydroxyphenyl)-2-oxoethyl)thio)pyrimidin-4(3H)-one (5c) and 4-(2-((4-(benzo[d][1,3]dioxol-5-ylmethyl)-5-ethyl-6-oxo-1,6-dihydropyrimidin-2-yl)thio)acetyl)phenylbenzo[d][1,3]dioxole-5-carboxylate (5r) were selected for further study. It was found that all of them had little toxicity to peripheral blood mononuclear cell (PBMC), and had a good inhibitory effect on the replication of HIV-1 protease inhibitor resistant strains, fusion inhibitor resistant strains and nucleosides reverse transcriptase inhibitor resistant strains, as well as on clinical isolates. Besides, compound 5b and 5c showed inhibition of HIV-1 RT RNA-dependent DNA polymerization activity and DNA-dependent DNA polymerization activity, while compound 5r only showed inhibition of HIV DNA-dependent DNA polymerization activity, which was different from classical reverse transcriptase inhibitors. Our study which offered the preliminary structure-activity relationships and modeling studies of these new compounds has provided the valuable avenues for future molecular optimization.
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http://dx.doi.org/10.1016/j.bioorg.2020.104041DOI Listing
September 2020

Callicarpins, Two Classes of Rearranged -Clerodane Diterpenoids from Plants Blocking NLRP3 Inflammasome-Induced Pyroptosis.

J Nat Prod 2020 07 6;83(7):2191-2199. Epub 2020 Jul 6.

Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming, Yunnan 650091, People's Republic of China.

Callicarpins A-D (-), possessing an unprecedented A--clerodane scaffold with a bicyclo[5.4.0]undecane ring system, and callicarpins E-G (-), with 5/6-fused -clerodane diterpenoid skeletons, were isolated from and . Their structures were elucidated by comprehensive spectroscopic data, X-ray crystal diffraction, chemical derivatization, and electronic circular dichroism (ECD) data. Putative biosynthetic pathways for these callicarpins are proposed. Compounds , , and - showed potent inhibitory effects against the NLRP3 inflammasome with IC values from 1.4 to 5.3 μM, and significantly blocked NLRP3 inflammasome-induced pyroptosis by inhibiting Casp-1 activation and IL-1β secretion in J774A.1 cells.
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http://dx.doi.org/10.1021/acs.jnatprod.0c00288DOI Listing
July 2020

Luteolin-7-methylether from Leonurus japonicus inhibits estrogen biosynthesis in human ovarian granulosa cells by suppression of aromatase (CYP19).

Eur J Pharmacol 2020 Jul 29;879:173154. Epub 2020 Apr 29.

Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China. Electronic address:

Leonurus japonicus (motherwort) has been widely used to treat gynecological disorders, in which estrogen is often dysregulated, for a long time in China and other Asian countries. However, the chemical constituents and mechanisms underlying the activity of this medicinal plant are not fully understood. Seventeen of forty-six tested natural products from L. japonicus showed stimulatory or inhibitory effects on estrogen biosynthesis with different potency in human ovarian granulosa-like KGN cells. Luteolin-7-methylether (XLY29) potently inhibited 17β-estradiol production (IC: 5.213 μM) by decreasing the expression of aromatase, the only enzyme in vertebrates that catalyzes the biosynthesis of estrogens, but had no effect on the catalytic activity of aromatase. XLY29 decreased the expression of aromatase promoter I.3/II, and suppressed the phosphorylation of cAMP response element-binding protein. XLY29 potently inhibited phosphorylation of p38 mitogen-activated protein kinase and AKT but had no effect on phosphorylation of extracellular signal-regulated kinase and c-Jun N-terminal kinase. XLY29 also decreased the serum 17β-estradiol level and disturbed estrous cycle in mice. These results suggest that modulation of estrogen biosynthesis is a novel effect of L. japonicus, and XLY29 warrants further investigation as a new therapeutic means for the treatment of estrogen-related diseases.
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http://dx.doi.org/10.1016/j.ejphar.2020.173154DOI Listing
July 2020

Controlling the selectivity of an intramolecular Friedel-Crafts alkylation with alkenes using selenium under mild conditions.

Org Biomol Chem 2020 06 19;18(21):4034-4045. Epub 2020 Mar 19.

Key Laboratory of Medicinal Chemistry for Natural Resources, Ministry of Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming, 650091 China.

An efficiently divergent intramolecular Friedel-Crafts alkylation by unactivated alkenes with seleniranium ion-controlled Markovnikov/anti-Markovnikov specificities under mild conditions has been investigated. 2-Benzoxepin, isochroman, and isochromene can be produced in one-pot procedures from the same substrate in high yields and with high regio- and stereospecificity. The products are challenging to access via 7-endo-trig carbocyclizations and by 7-endo-trig carbocyclization/rearrangement/6-exo-trig oxycyclization and 6-exo-trig carbocyclization/deselenenylation reaction sequences, respectively. Mechanistic experiments indicated that in addition to the stereospecific anti-addition processes of the cyclization reactions, the formation of a stable carbocation after ring opening of the seleniranium ion leads to an NPSP-mediated 7-endo-trig carbocyclization; the steric hindrance of the seleniranium intermediate controls the regioselectivity when using TPSCA at 60 °C, which promotes 6-exo-trig carbocyclization. Two distinct catalytic cycles were proposed, and the structures of transition states and products were identified by ab initio calculations and X-ray analyses.
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http://dx.doi.org/10.1039/d0ob00257gDOI Listing
June 2020

Synthesis and anti-inflammatory evaluation of new chalcone derivatives bearing bispiperazine linker as IL-1β inhibitors.

Bioorg Chem 2020 05 10;98:103748. Epub 2020 Mar 10.

College of Pharmaceutical Science, Yunnan University of Chinese Medicine, Kunming 650500, PR China. Electronic address:

In this work, a series of novel chalcone derivatives bearing bispiperazine linker have been synthesized and in vitro anti-inflammatory, cytotoxic activity and anti-inflammatory mechanism have been screened. The results indicated that most bispiperazinochalcone derivatives displayed good inhibition of NO (IC < 20 μM) and low cytotoxicity (CC > 40 μM), and selectively inhibited the production of IL-1β via inhibiting NLRP3 inflammasome activation, as promising candidate compounds for the treatment of NLRP3 inflammasome-driven diseases.
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http://dx.doi.org/10.1016/j.bioorg.2020.103748DOI Listing
May 2020

Synthesis and Biological Evaluation of Heterocyclic Substituted Bis(indolyl)methanes.

Curr Org Synth 2020 ;17(2):144-150

College of Pharmaceutical Science, Yunnan University of Chinese Medicine, Kunming 650500, China.

Background: Bis(indolyl)methane derivatives are widely found in nature with a broad range of biological and pharmacological activities. The development of techniques for the synthesis and functionalization of bis(indolyl)methanes have attracted more and more attention in recent years.

Objective: To study the synthesis and biological activity of heterocyclic substituted bis(indolyl)methanes.

Materials And Methods: A series of heterocyclic substituted bis(indolyl)methanes (3a-3p) have been prepared by condensation reaction of indole and heterocyclic aldehydes catalyzed by boron trifluoride etherate with high yields. Preliminary in vitro anti-inflammatory in lipopolysaccharide (LPS)-stimulated RAW-264.7 macrophages and cytotoxic activity against human tumor cell lines (A549, Hela and SGC7901) by MTT assay were tested.

Results: The result indicated that heterocyclic substituted bis(indolyl)methanes showed good antiinflammatory and selective cytotoxic activity. Especially, compounds 3o, 3p and 3q displayed similar inhibitory effect on the generation of NO to positive control dexamethasone, and compound 3q displayed similar selective cytotoxic activity to 5-FU.

Conclusion: Heterocyclic substituted bis(indolyl)methanes may be used as potential anti-inflammatory and anticancer leads.
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http://dx.doi.org/10.2174/1570179417666200124103400DOI Listing
May 2021

Clerodane diterpenoids with potential anti-inflammatory activity from the leaves and twigs of Callicarpa cathayana.

Chin J Nat Med 2019 Dec;17(12):953-962

Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming 650091, China. Electronic address:

Phytochemical investigation of the leaves and twigs of Callicarpa cathayana led to the isolation of six new clerodane diterpenoids, cathayanalactones A-F (1-6), together with seven analogues (7-13). Their structures were established by extensive NMR analyses together with experimental and calculated ECD spectra analyses. Compounds 1, 2, 3, 7 and 11 showed inhibitory activities on lipopolysaccharide-induced nitric oxide production in RAW264.7 cells.
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http://dx.doi.org/10.1016/S1875-5364(19)30118-9DOI Listing
December 2019

Elucidation of the Structure of Pseudorubriflordilactone B by Chemical Synthesis.

J Am Chem Soc 2020 08 3;142(32):13701-13708. Epub 2020 Aug 3.

State Key Laboratory of Bioorganic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China.

Rubriflordilactone B () is a schinortriterpenoid isolated by Sun and colleagues, which possesses a tetrasubstituted benzene moiety and eight stereocenters. The previous synthesis of by Li and co-workers uncovered the existence of its naturally occurring stereoisomer "pseudorubriflordilactone B". Here we report a collaborative study by the two groups that elucidates the structure of pseudorubriflordilactone B to be 16,17-bis--rubriflordilactone B (). Chemical synthesis served as an important tool in the structure determination. Taking advantage of a modular synthetic route, we systematically "mutated" the configurations of C-23, C-22, C-20, and C-16/C-17 located at the right-hand domain of , and thus prepared its 15 stereoisomers for spectrum comparison. The H NMR spectra of synthetic in deuterated chloroform and pyridine were identical to those of authentic pseudorubriflordilactone B, respectively. This synthetic sample displayed anti-HIV activity (EC = 0.288 μM) in vitro.
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http://dx.doi.org/10.1021/jacs.9b09699DOI Listing
August 2020

Molecular networking-based strategy for the discovery of polyacetylated 18-norspirostanol saponins from Trillium tschonoskii maxim.

Phytochemistry 2019 Dec 18;168:112125. Epub 2019 Sep 18.

State Key Laboratory of Phytochemistry and Plant Resources in West China, Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China. Electronic address:

Nine undescribed polyacetylated 18-norspirostanol saponins, trilliumosides A‒J, were obtained after a guidance based on a molecular networking strategy from the rhizomes of Trillium tschonoskii. Their structures were established by analysis of comprehensive spectroscopic data and chemical methods after their isolation in pure form. All isolated saponins were evaluated for their cytotoxicities against five selected human cancer cell lines (Huh7,A549,MCF-7,HepG2, and MOLT-4) and anti-inflammatory effects on a lipopolysaccharide (LPS)-stimulated NO production model in RAW264.7 macrophages. Trilliumoside D showed significant cytotoxicity against MOLT-4 cell lines with an IC value of 1.0 ± 0.1 μM, whereas trilliumosides H and I displayed remarkable anti-inflammatory effects on NO production with inhibitory rates of 56.3 ± 1.5 and 56.2 ± 2.2% at the concentration of 1.0 μM, respectively.
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http://dx.doi.org/10.1016/j.phytochem.2019.112125DOI Listing
December 2019

Density functional theory, molecular docking and bioassay studies on ()-2-hydroxy-N-(2,3,4,)-1,3,4 trihydroxyicos-16-en-2-yl)tricosanamide.

Heliyon 2019 Aug 2;5(8):e02038. Epub 2019 Aug 2.

Department of Chemistry, University of Education, Okara Campus, Okara, Punjab, Pakistan.

A novel indigoferamide-A, earlier isolated from the seeds of Wall was characterized using density functional theory, molecular docking and bioassays studies. Density functional theory calculations were performed at B3LYP/6-31G(d,p) to gain geometric insight of the compound. Conformational analyses have been performed around three important dihedral angles to explore the lowest energy structure and conformer. The simulated vibrational spectrum of the compound at B3LYP/6-31G(d,p) was scaled with two scaling factors, and the scaled harmonic vibrations shows nice correlation with the experimental values. H and C NMR chemical shifts were calculated using Cramer's re-parameterized function W04 at 6- 31G(d,p) basis set. Several conformers lying within 2 kcal mol of the minimum energy conformer were considered; however, the chemical shifts were not significantly different among these conformers. The Gaussian averaged theoretical H and C chemical shifts correlate nicely with the experimental data. Electronic properties such as band gap, ionization potential and electron affinities were also simulated for the first time, however, no comparison could be made with the experiment. The compound was also screened for urease, antiglycation activities and the theoretical explanation of the results is provided based on molecular docking simulations.
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http://dx.doi.org/10.1016/j.heliyon.2019.e02038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6690558PMC
August 2019

Chemical Space and Biological Target Network of Anti-Inflammatory Natural Products.

J Chem Inf Model 2019 01 20;59(1):66-73. Epub 2018 Dec 20.

Key Laboratory of Medicinal Chemistry for Natural Resources, Ministry of Education and Yunnan Province, School of Chemical Science and Technology , Yunnan University , 2Rd. Cuihubei , Kunming 650091 , China.

Natural products (NPs) are a promising source of anti-inflammatory molecules for the development of drugs. Despite there being an abundance of reports of large numbers of NPs having bioactivity in preliminary cell-based assays of anti-inflammatory potential, their further optimization and exploration are limited by the lack of a comprehensive understanding of their effective scaffold structure or biological targets. To facilitate target-based studies of anti-inflammatory NPs, the details of 665 NPs reported to have anti-inflammatory activity were extracted from the literature and compiled into a data set we termed InflamNat. The physicochemical properties of the NPs were analyzed, and the distribution of their structures and scaffolds is presented. A compound-target network was constructed from data in the PubChem Bioassay database. The results demonstrated that, compared to natural anticancer compounds in the NPACT database, compounds from the InflamNat data set contained a comparable distribution of compound types but with a higher proportion satisfying Lipinski's rule. The all-atom structures and scaffold of the compounds were diverse and barely convergent, with flavonoids and triterpenoids being the groups with the greatest abundance. The biological targets of the InflamNat compounds were identified as belonging to a variety of protein families that had varied function. Seventy-two percent of InflamNat compounds involved in the network were identified as having more than one biological target, highlighting the potential for multitarget anti-inflammatory drug development. In conclusion, anti-inflammatory NPs provide a good library for the screening of target-based leads or fragment-based drug design. Thus, elucidation of their biological targets is fundamental for either a specific single-target or multitarget drug development strategy. Meanwhile, a large proportion of the chemical space of anti-inflammatory NPs is still unexplored, with novel active scaffolds remaining to be discovered.
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http://dx.doi.org/10.1021/acs.jcim.8b00560DOI Listing
January 2019

Premnafulvol A: A Diterpenoid with a 6/5/7/3-Fused Tetracyclic Core and Its Biosynthetically Related Analogues from Premna fulva.

Org Lett 2018 10 26;20(19):6314-6317. Epub 2018 Sep 26.

Key Laboratory of Medicinal Chemistry for Natural Resource of Ministry of Education and Yunnan Province, School of Chemical Science and Technology , Yunnan University , Kunming 650091 , China.

Premnafulvol A (1), a unique diterpenoid featuring a 6/5/7/3-fused tetracyclic carbon skeleton, with three biosynthetically related analogues, premnafulvols B-D (2-4), were isolated from the aerial parts of Premna fulva. Structures of 1-4 were established by a combination of extensive spectroscopic analyses, quantum chemical calculations, and X-ray crystallography. Plausible biosynthetic pathways of 1-4 were proposed. Interestingly, 2 and 3 exhibited opposite effects on estrogen biosynthesis in human ovarian granulosa-like KGN cells by modulating the expression of aromatase.
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http://dx.doi.org/10.1021/acs.orglett.8b02845DOI Listing
October 2018

Immune-inhibitive phenyl-C substituent aporphine alkaloids from Thalictrum cirrhosum.

Fitoterapia 2018 Jul 28;128:247-252. Epub 2018 May 28.

State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, PR China; Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming 650091, PR China. Electronic address:

Five new phenyl-C substituent aporphine alkaloids, 6aR-2'-methoxycarbonyl-thaliadin (1), 6aR-2'-carboxyl-thaliadin (2), 6aR-3-methoxy-hernandalinol (3), 6aS-1,3,10-trimethoxy-natalamine (4), and 3-methoxy-2'-methoxycarbonyl-oxohernandalincin (5), together with sixteen known isoquinoline alkaloids (6-21) were isolated from the whole herb of Thalictrum cirrhosum (Levl.). Their structures were elucidated by extensive spectroscopic measurements, and six isoquinoline alkaloids showed significant inhibitory activity on concanavalin A-stimulated splenocytes proliferation with IC values 36-44 μM by the immunosuppressive bioassay.
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http://dx.doi.org/10.1016/j.fitote.2018.05.030DOI Listing
July 2018

In Vitro Human Dihydroorotate Dehydrogenase Inhibitory, Anti-inflammatory and Cytotoxic Activities of Alkaloids from the Seeds of Nigella glandulifera.

Planta Med 2018 Sep 5;84(14):1013-1021. Epub 2018 Apr 5.

State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China.

Four new dolabellane-type diterpene alkaloids, glandulamines A - D (1:  - 4: ), together with twelve known compounds (5:  - 16: ), were isolated from the seeds of using repeated column chromatography and semipreparative HPLC. The structures of 1:  - 16: were elucidated based on NMR data analysis, HRMS experiments and other spectroscopic interpretations. The absolute configuration of 5: was determined by single-crystal X-ray diffraction data for the first time. Compounds 10: and 12: showed human dihydroorotate dehydrogenase inhibitory activity with IC values of 61.1 ± 5.3 and 45.9 ± 3.0 µM, respectively. Molecular docking of the active compound 12: and positive control teriflunomide on the inhibitor-binding site of human dihydroorotate dehydrogenase was subsequently performed to visualize the interaction pattern. In addition, compounds 8: and 10: exhibited inhibitory effects against lipopolysaccharide-induced nitric oxide production with inhibition rates of 61 and 41%, respectively, at the concentration of 10 µM. Compounds 9: and 12: showed cytotoxic activities with cell viability varying from 29 ~ 57% at 100 µM against T98G, U87, U251, and GL261 glioma cancer cell lines. These data provide new insights on the pharmacologically active compounds of this plant widely used in folk medicine.
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http://dx.doi.org/10.1055/a-0598-4866DOI Listing
September 2018

Isolation, Characterization, and Structure-Activity Relationship Analysis of Abietane Diterpenoids from Callicarpa bodinieri as Spleen Tyrosine Kinase Inhibitors.

J Nat Prod 2018 04 26;81(4):998-1006. Epub 2018 Mar 26.

Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education and Yunnan Province, School of Chemical Science and Technology , Yunnan University , Kunming , Yunnan 650091 , People's Republic of China.

Species belonging to the genus Callicarpa are used traditionally in Chinese medicine for the treatment of inflammation, rheumatism, and pain. Investigation of the leaves and twigs of Callicarpa bodinieri resulted in the isolation of nine new abietane diterpenoids, bodinieric acids A-I (1-9), along with six known compounds (10-15). The structures of 1-9 were elucidated on the basis of the interpretation of their HRESIMS and NMR data and by ECD calculations. To explore the potential therapeutic target of this plant for immune-mediated disease, the inhibitory activities of the isolates obtained were determined against 13 kinase enzymes. Eight compounds exhibited moderate inhibitory effects on spleen tyrosine kinase (SYK), and the IC values of compounds 2 and 6 were 7.2 and 10.7 μM, respectively. In addition, a preliminary structure-activity relationship of this scaffold was analyzed with both molecular docking and a 3D-QSAR pharmacophore model.
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http://dx.doi.org/10.1021/acs.jnatprod.7b01082DOI Listing
April 2018

Schinortriterpenoids with Identical Configuration but Distinct ECD Spectra Generated by Nondegenerate Exciton Coupling.

Org Lett 2018 03 2;20(6):1500-1504. Epub 2018 Mar 2.

State Key Laboratory of Phytochemistry and Plant Resources in West China , Kunming Institute of Botany, Chinese Academy of Sciences , Kunming 650201 , Yunnan , People's Republic of China.

Ten schinortriterpenoids with biogenetically related lancischiartane scaffolds, including the first 3-norlancischiartane (1) with unusual configuration inversions occurring at C-1 and C-10, were isolated from Schisandra lancifolia. Unusual ECD curve patterns observed in 6-8 were confirmed to be caused by nondegenerate exciton coupling, suggesting that ECD spectrum empirical comparison should be used with caution in configuration determination. Additionally, structure revision of 2, originally proposed as arisanlactone A, was completed using NMR computation and X-ray diffraction analysis.
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http://dx.doi.org/10.1021/acs.orglett.8b00149DOI Listing
March 2018

SJP-L-5 inhibits HIV-1 polypurine tract primed plus-strand DNA elongation, indicating viral DNA synthesis initiation at multiple sites under drug pressure.

Sci Rep 2018 02 7;8(1):2574. Epub 2018 Feb 7.

Key Laboratory of Bioactive Peptides of Yunnan Province/Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, 650223, China.

In a previous study the small molecule SJP-L-5 that inhibits HIV replication, has been shown to block uncoating of the viral capsid. Continued study showed that SJP-L-5 might hinder HIV capsid uncoating by blocking the completion of reverse transcription. However, to date, the mechanism has not been fully elucidated. Here, the effects of SJP-L-5 for reverse transcription were explored via quantitative PCR, DIG-labelled ELISA, fluorescent resonance energy transfer, and Southern blot assays. We also analyzed the resistance profile of this compound against reverse transcriptase. Our results show that SJP-L-5 preferentially inhibits PPT primed plus-strand DNA synthesis (EC = 13.4 ± 3.0 μM) over RNA primed minus-strand DNA synthesis (EC > 3,646 μM), resulting in formation of five segmented plus-strand DNA and loss of HIV DNA flap, suggesting failure of both nuclear import and integration. Moreover, resistance study evidenced that SJP-L-5 requires the amino acid residues Val108 and Tyr181 to exert an inhibitory effect. These results indicate SJP-L-5 as a new non-nucleoside reverse transcriptase inhibitor that inhibits HIV-1 polypurine tract primed plus-strand DNA synthesis, initiating HIV-1 down-stream plus-strand DNA synthesis at multiple sites under drug pressure.
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http://dx.doi.org/10.1038/s41598-018-20954-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5803243PMC
February 2018

Phytochemistry and pharmacology of the genus Leonurus: The herb to benefit the mothers and more.

Phytochemistry 2018 Mar 12;147:167-183. Epub 2018 Jan 12.

Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan University, Kunming 650091, PR China. Electronic address:

Plants belonging to the genus Leonurus, also named motherwort, are traditionally used for anti-gynecological disorder in East Asia, and for sedative in Europe. Chemical investigation of the genus Leonurus not only enriched the natural products library, but also enlarged the pharmacological application of this traditional herb. In this review, we systematically summarized the structures of 259 compounds isolated from the genus Leonurus, featured with 147 labdane diterpenoids. The reported bioactivity studies up to 2017 are presented in the second part, with the main focus on the isolated compounds and also concerning the extracts. In addition to the traditional uterine contraction and sedative activity, recently the cardiovascular protection effect of leonurine has drawn most attention. Other than that, neuroprotection, anti-inflammation, anti-cancer, anti-platelet aggregation and many other activities have been assigned to various compounds from the genus Leonurus. Among 70 bioactivity references cited in this review, 57% of them were concentrated on two alkaloids (leonurine and stachydrine), whereas only 20% are about the 147 diterpenoids. Anti-inflammation is the major bioactivity discovered so far for the labdane diterpenoids from the genus Leonurus, whose further therapeutic potential still remains for exploration.
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http://dx.doi.org/10.1016/j.phytochem.2017.12.016DOI Listing
March 2018

Hispanane-Type Diterpenoid and Secoiridoid Glucosides from Viburnum cylindricum.

Chem Biodivers 2018 Jan 5;15(1). Epub 2018 Jan 5.

Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, School of Chemical Science and Technology, Yunnan University, Kunming, 650091, P. R. China.

Three hitherto unknown compounds, including one new hispanane-type diterpenoid glucoside, namely viburnumoside (1), two new secoiridoid glucosides, 7α-galloyloxysweroside (2), and 7β-galloyloxysweroside (3), together with ten known compounds (4 - 13) were isolated from the ethanol extract of twigs and leaves of Viburnum cylindricum. Their structures were elucidated on the basis of extensive spectroscopic studies, and the absolute configuration of compound 1 was confirmed by the experimental and calculated electronic circular dichroism (ECD) data.
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http://dx.doi.org/10.1002/cbdv.201700418DOI Listing
January 2018
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