Publications by authors named "Xing-Jie Zhang"

35 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

Novel dual-mode antitumor chlorin-based derivatives as potent photosensitizers and histone deacetylase inhibitors for photodynamic therapy and chemotherapy.

Eur J Med Chem 2021 May 17;217:113363. Epub 2021 Mar 17.

School of Pharmacy, Second Military Medical University, Shanghai, 200433, China; Department of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, 350108, China; School of Pharmacy, Ningxia Medical University, Yinchuan, 750004, China. Electronic address:

The combination of photodynamic therapy (PDT) and chemotherapy is a prospective strategy to improve antitumor efficacy. Herein, a series of novel cytotoxic chlorin-based derivatives as dual photosensitizers (PSs) and histone deacetylase inhibitors (HDACIs) were synthesized and investigated for biological activity. Among them, compound 15e showed definite HDAC2 and 10 inhibitory activities by up-regulating expression of acetyl-H4 and highest phototoxicity and dark-toxicity, which was more phototoxic than Talaporfin as a PS while with stronger dark-toxicity compared to vorinostat (SAHA) as a HDACI. The biological assays demonstrated that 15e was liable to enter A549 cells and localized in mitochondria, lysosomes, golgi and endoplasmic reticulum (ER) etc. multiple organelles, resulting in higher cell apoptosis rate and ROS production compared to Talaporfin. Moreover, it could induce tumor cell autophagy as a dual PS and HDACI. All results suggested that compound 15e could be applied as a potential dual cytotoxic drug for PDT and chemotherapy.
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http://dx.doi.org/10.1016/j.ejmech.2021.113363DOI Listing
May 2021

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

Bioorg Chem 2021 04 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

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

Design, synthesis and biological evaluation of novel 3-hexyloxy chlorin e-based 15- or 13-amino acid derivatives as potent photosensitizers for photodynamic therapy.

Eur J Med Chem 2020 Dec 18;207:112715. Epub 2020 Aug 18.

School of Pharmacy, Second Military Medical University, Shanghai, 200433, China; School of Pharmacy, Ningxia Medical University, Ningxia, 750004, China. Electronic address:

This study aimed to improve the biological effectiveness and pharmacokinetic properties of chlorin e, a second-generation photosensitizer (PS), for tumor photodynamic therapy (PDT). Herein, the novel 3-hexyloxy chlorin e-based 15- or 13-amino acid derivatives 3a, 3b, 3c and 8 were synthesized and their photophysical properties and in vitro bioactivities such as phototoxicity against A549, HeLa and melanoma B16-F10 cells, reactive oxygen species (ROS) production and subcellular localization were evaluated. In addition, preferred target compounds were also investigated for their in vivo pharmacokinetic in SD rats and in vivo antitumor efficacies in C57BL/6 mice bearing melanoma B16-F10 cells. Apparently, simultaneous introduction of amino acid residue and n-hexyloxy chain in chlorin e made a significant improvement in photophysical properties, ROS production, in vitro and in vivo PDT efficacy. Encouragingly, all target compounds showed higher in vitro phototoxicity than Talaporfin, and that 3c (15-Lys) exhibited strongest phototoxicity and highest dark toxicity/phototoxicity ratio, followed by 8 (13-Asp), 3a (15-Asp) and 3b (15-Glu). Moreover, in vivo PDT antitumor efficacy of 3a, 3c and 8 was all better than that of Talaporfin, and that both 3c and 8 had stronger PDT antitumor efficiency than 3a. The overall results suggested that these novel 3-hexyloxy chlorin e-based 15- or 13-amino acid derivatives, especially 3c and 8, might be potential antitumor candidate drugs for clinical treatment of melanoma by PDT.
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http://dx.doi.org/10.1016/j.ejmech.2020.112715DOI Listing
December 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

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

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

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

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

Highly oxygenated lanostane-type triterpenoids and their bioactivity from the fruiting body of Ganoderma gibbosum.

Fitoterapia 2017 Jun 11;119:1-7. Epub 2017 Mar 11.

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, School of Chemical Science and Technology, and State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Yunnan University, Kunming 650091, PR China. Electronic address:

Eight new highly oxygenated lanostane triterpenes, gibbosic acids A-H (1-8), along with three known ones (9-11), were isolated from the fruiting body of Ganoderma gibbosum. The structures of new isolates were assigned by NMR and HRESIMS experiments. The absolute configurations of 1 were further confirmed by single crystal X-ray diffraction data and computational ECD methods. Immunoregulatory effect and anti-inflammatory activities of these compounds were screened in murine lymphocyte proliferation assay and in lipopolysaccharide (LPS)-stimulated RAW-264.7 macrophages, respectively. Compound 2 exhibited immunostimulatory effect both in lymphocyte proliferation assay without any induction and ConA-induced mitogenic activity of T-lymphocyte, and the proportion of lymphocyte proliferation at the concentration of 0.1μM are 20.01% and 21.40%, respectively.
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http://dx.doi.org/10.1016/j.fitote.2017.03.007DOI Listing
June 2017

Synthesis and Anti-HIV-1 Activity Evaluation for Novel 3a,6a-Dihydro-1H-pyrrolo[3,4-c]pyrazole-4,6-dione Derivatives.

Molecules 2016 Sep 8;21(9). Epub 2016 Sep 8.

CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, China.

The search for new molecular constructs that resemble the critical two-metal binding pharmacophore and the halo-substituted phenyl functionality required for HIV-1 integrase (IN) inhibition represents a vibrant area of research within drug discovery. As reported herein, we have modified our recently disclosed 1-[2-(4-fluorophenyl)ethyl]-pyrrole-2,5-dione scaffolds to design 35 novel compounds with improved biological activities against HIV-1. These new compounds show single-digit micromolar antiviral potencies against HIV-1 and low toxicity. Among of them, compound 9g and 15i had potent anti-HIV-1 activities (EC50 < 5 μM) and excellent therapeutic index (TI, CC50/EC50 > 100). These two compounds have potential as lead compounds for further optimization into clinical anti-HIV-1 agents.
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http://dx.doi.org/10.3390/molecules21091198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6274355PMC
September 2016

SJP-L-5, a novel small-molecule compound, inhibits HIV-1 infection by blocking viral DNA nuclear entry.

BMC Microbiol 2015 Dec 2;15:274. Epub 2015 Dec 2.

Sun Yat-Sen University, Guangzhou, 510275, P. R. China.

Background: Small-molecule compounds that inhibit human immunodeficiency virus type 1 (HIV-1) infection can be used not only as drug candidates, but also as reagents to dissect the life cycle of the virus. Thus, it is desirable to have an arsenal of such compounds that inhibit HIV-1 infection by various mechanisms. Until now, only a few small-molecule compounds that inhibit nuclear entry of viral DNA have been documented.

Results: We identified a novel, small-molecule compound, SJP-L-5, that inhibits HIV-1 infection. SJP-L-5 is a nitrogen-containing, biphenyl compound whose synthesis was based on the dibenzocyclooctadiene lignan gomisin M2, an anti-HIV bioactive compound isolated from Schisandra micrantha A. C. Smith. SJP-L-5 displayed relatively low cytotoxicity (50% cytoxicity concentrations were greater than 200 μg/ml) and high antiviral activity against a variety of HIV strains (50% effective concentrations (EC50)) of HIV-1 laboratory-adapted strains ranged from 0.16-0.97 μg/ml; EC50s of primary isolates ranged from 1.96-5.33 μg/ml). Analyses of the viral DNA synthesis indicated that SJP-L-5 specifically blocks the entry of the HIV-1 pre-integration complex (PIC) into the nucleus. Further results implicated that SJP-L-5 inhibits the disassembly of HIV-1 particulate capsid in the cytoplasm of the infected cells.

Conclusions: SJP-L-5 is a novel small-molecule compound that inhibits HIV-1 nuclear entry by blocking the disassembly of the viral core.
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http://dx.doi.org/10.1186/s12866-015-0605-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4667461PMC
December 2015

Azvudine, a novel nucleoside reverse transcriptase inhibitor showed good drug combination features and better inhibition on drug-resistant strains than lamivudine in vitro.

PLoS One 2014 21;9(8):e105617. Epub 2014 Aug 21.

Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China.

Azvudine is a novel nucleoside reverse transcriptase inhibitor with antiviral activity on human immunodeficiency virus, hepatitis B virus and hepatitis C virus. Here we reported the in vitro activity of azvudine against HIV-1 and HIV-2 when used alone or in combination with other antiretroviral drugs and its drug resistance features. Azvudine exerted highly potent inhibition on HIV-1 (EC(50)s ranging from 0.03 to 6.92 nM) and HIV-2 (EC(50)s ranging from 0.018 to 0.025 nM). It also showed synergism in combination with six approved anti-HIV drugs on both C8166 and PBMC. In combination assay, the concentrations of azvudine used were 1000 or 500 fold lower than other drugs. Azvudine also showed potent inhibition on NRTI-resistant strains (L74V and T69N). Although M184V caused 250 fold reduction in susceptibility, azvudine remained active at nanomolar range. In in vitro induced resistant assay, the frequency of M184I mutation increased with induction time which suggests M184I as the key mutation in azvudine treatment. As control, lamivudine treatment resulted in a higher frequency of M184I/V given the same induction time and higher occurrence of M184V was found. Molecular modeling analysis suggests that steric hindrance is more pronounced in mutant M184I than M184V due to the azido group of azvudine. The present data demonstrates the potential of azvudine as a complementary drug to current anti-HIV drugs. M184I should be the key mutation, however, azvudine still remains active on HIV-1LAI-M184V at nanomolar range.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0105617PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4140803PMC
May 2015

DB-02, a C-6-cyclohexylmethyl substituted pyrimidinone HIV-1 reverse transcriptase inhibitor with nanomolar activity, displays an improved sensitivity against K103N or Y181C than S-DABOs.

PLoS One 2013 25;8(11):e81489. Epub 2013 Nov 25.

Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, P. R. China ; University of Chinese Academy of Sciences, Beijing, P. R. China.

6-(cyclohexylmethyl)-5-ethyl-2-((2-oxo-2-phenylethyl)thio)pyrimidin-4(3H)-one (DB-02) is a member of the newly reported synthetic anti-HIV-1 compounds dihydro-aryl/alkylsulfanyl-cyclohexylmethyl-oxopyrimidines, S-DACOs. In vitro anti-HIV-1 activity and resistance profile studies have suggested that DB-02 has very low cytotoxicity (CC50>1mM) to cell lines and peripheral blood mononuclear cells (PBMCs). It displays potent anti-HIV-1 activity against laboratory adapted strains and primary isolated strains including different subtypes and tropism strains (EC50s range from 2.40 to 41.8 nM). Studies on site-directed mutagenesis, genotypic resistance profiles revealed that V106A was the major resistance contributor for the compound. Molecular docking analysis showed that DB-02 located in the hydrophobic pocket with interactions of Lys101, Val106, Leu234, His235. DB-02 also showed non-antagonistic effects to four approved antiretroviral drugs. All studies indicated that DB-02 would be a potential NNRTI with low cytotoxicity and improved activity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0081489PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3839930PMC
August 2014

Structural modifications of 5,6-dihydroxypyrimidines with anti-HIV activity.

Bioorg Med Chem Lett 2012 Dec 2;22(23):7114-8. Epub 2012 Oct 2.

State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, PR China.

A series of 5,6-dihydroxypyrimidine analogs were synthesized and evaluated for their anti-HIV activity in vitro. Among all of the analogs, several compounds exhibited significant anti-HIV activity, especially 1b and 1e, which showed the most potent anti-HIV activity with EC(50) values of 0.14 and 0.15 μM, and TI (therapeutic index) values of >300 and >900, respectively. Further docking studies revealed that the representative compounds 1e and 3a could meet the HIV-1 integrase inhibition minimal requirements of a chelating domain (two metal ions) and an aromatic domain (π-π stacking interactions).
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http://dx.doi.org/10.1016/j.bmcl.2012.09.070DOI Listing
December 2012

Benzophenone glycosides and epicatechin derivatives from Malania oleifera.

Fitoterapia 2012 Sep 17;83(6):1068-71. Epub 2012 May 17.

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

A new benzophenone C-glycoside, malaferin A (1), and two new epicatechin derivatives, malaferin B (2) and malaferin C (3), together with five known compounds were isolated from Malania oleifera. In addition, (-)-epicatechin-3-O-benzoate (6) was isolated for the first time from a natural resource. Structures of 1-3 were determined on the basis of their spectroscopic methods, including 1D and 2D NMR techniques. All of the compounds were evaluated for anti-HIV activities.
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http://dx.doi.org/10.1016/j.fitote.2012.05.006DOI Listing
September 2012

Daphnane-type diterpene esters with cytotoxic and anti-HIV-1 activities from Daphne acutiloba Rehd.

Phytochemistry 2012 Mar 21;75:99-107. Epub 2011 Dec 21.

State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650204, People's Republic of China.

Seven previously unreported daphnane-type diterpene esters named acutilobins A-G, together with 12 known ones, were isolated from EtOAc extract of Daphne acutiloba Rehd. Their structures were elucidated based on the spectroscopic data. The cytotoxic and anti-HIV-1 activities of these daphnane-type diterpene esters were evaluated through bioassays. Fourteen of these isolates exhibited definite cytotoxic activities against the five human tumor cell lines HL-60, SMMC-7721, A-549, MCF-7, and SW480. Additionally, anti-HIV-1 activities were observed in 13 daphnane-type diterpene esters, among which acutilobins A-G exhibited significant anti-HIV-1 activities with EC₅₀ below 1.5 nM and SI over 10,000. Particularly, genkwanineVIII showed the strongest activity with EC₅₀ 0.17 nM and SI 187,010.
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http://dx.doi.org/10.1016/j.phytochem.2011.11.013DOI Listing
March 2012

Phenols with anti-HIV activity from Daphne acutiloba.

Planta Med 2012 Jan 11;78(2):182-5. Epub 2011 Oct 11.

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

The present paper describes the study of the phytochemical properties and anti-HIV activity of the phenolic isolates of the plateau medicinal plant Daphne acutiloba Rehd. (Thymelaeceae). Two new lignans named daphnenin (1) and daphnetone (2), along with 11 known ones, were isolated, and their structures were elucidated by 1D and 2DNMR spectroscopy aswell as HR‑ESI‑MS. In the anti-HIV activity study, daphnenin (1) and caffeic acid n-octadecyl ester (13) showed definite anti-HIVactivity with EC(50) values of 0.39 and 0.16 μg/mL, respectively.
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http://dx.doi.org/10.1055/s-0031-1280263DOI Listing
January 2012
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