• <tr id="yyy80"></tr>
  • <sup id="yyy80"></sup>
  • <tfoot id="yyy80"><noscript id="yyy80"></noscript></tfoot>
  • 99热精品在线国产_美女午夜性视频免费_国产精品国产高清国产av_av欧美777_自拍偷自拍亚洲精品老妇_亚洲熟女精品中文字幕_www日本黄色视频网_国产精品野战在线观看 ?

    Atramacronoids A-C,three eudesmanolide sesquiterpene-phenol hybrids with an unprecedented C-C linkage from the rhizomes of Atractylodes macrocephala

    2023-03-14 06:52:20HixinZhngJingrongLiJingungSiChengyDongQiLiMengYuLinglingQinLingyuLiChenxuZhoToZhngZhongmeiZou
    Chinese Chemical Letters 2023年1期

    Hixin Zhng,Jingrong Li,b,Jingung Si,Chengy Dong,Qi Li,Meng Yu,Lingling Qin,Lingyu Li,Chenxu Zho,d,To Zhng,*,Zhongmei Zou,*

    a Institute of Medicinal Plant Development,Chinese Academy of Medical Sciences & Peking Union Medical College,Beijing 100193,China

    b Medical Sciences,Guizhou Medical University,Guiyang 550000,China

    c China National Clinical Research Center for Neurological Diseases,Beijing Tiantan Hospital,Capital Medical University,Beijing 100193,China

    d School of Pharmacy,Henan University of Chinese Medicine,Zhengzhou 450000,China

    Keywords:Atractylodes macrocephala Compositae Sesquiterpene-phenol hybrids Anti-cancer Neutrophil elastase

    ABSTRACT Three eudesmanolide sesquiterpene-phenol hybrids,atramacronoids A-C (1-3),featuring an unusual 6/6/5/5/6 skeleton furnished by forming an unexpected C-8-C-16 linkage,were obtained from the rhizomes of Atractylodes macrocephala.Their structures and absolute configurations were elucidated by spectroscopic data analysis,chemical calculations,combined with X-ray diffractions.The plausible biosynthetic pathways for compounds 1-3 are proposed.Surprisingly,compound 1 exhibited cytotoxicity against SGC-7901 cells by inducing cells apoptosis,which might relate to the promotion of synthesis of neutrophil elastase.

    Sesquiterpene lactones,such as eudesmanolide,guaianolide,and germacranolide,have been widely reported from Compositae plants,with theα-methylene-γ-lactone moiety connected to other building blocks to form diverse structurally intriguing and biologically active adducts [1–7].Although the isolated sesquiterpene lactone oligomers present a dramatic increase [8],hybrids of sesquiterpene lactones especially eudesmanolide hybrids,are extraordinary rare.So far,only two types of eudesmanolide hybrids,eudesmanolide-furan [4] and eudesmanolide-alkaloid [9],have been isolated from natural resources.Structurally,both of them possessed the furan or alkaloid moiety linkage to eudesmanolide skeleton onlyviathe methyl at C-11.Due to the fascinating structures,eudesmanolide hybrids have attracted broad interest from natural products and synthetic chemists since 2019 [6,9].

    A recently research published inCellrevealed that neutrophil elastase (NE) was a major anticancer protein released by human neutrophils,which specifically activated the cell death pathway in cancer cells.Researchers observed that NE initiated a complex cancer killing program that inhibited cell survival pathways,induced DNA damage,increased the production of mitochondrial reactive oxygen species,and ultimately activated programmed cell death,that is so-called apoptosis [10].It made NE became a hot topic in various scientific communities.However,apart from these inspiring reports,the presence and value of natural products possessing effect on NE remain largely unexplored.

    The genusAtractylodes(Compositae) is represented by a relatively limited number of species and mainly distributed in eastern region of Asia.Atractylodes macrocephalaKoidz,is a perennial herb belonging to theAtractylodesgenus,which is widely distributed in China,Korea,and Japan [11].The rhizomes ofA.macrocephalaare the certified plant source for “Bai zhu”,a common traditional Chinese medicine that is often used for the treatment of splenic hypofunction with inappetence,edema,spontaneous sweating,etc.[12].Nowadays,“Bai zhu” is also one of the ingredients inQingfei Paidudecoction,a key traditional Chinese medicine (TCM) formula used for treatment of COVID-19 in China [13].Extensive phytochemical studies fromA.macrocephalarevealed that sesquiterpenes were the main chemical constituents [14].However,there was remained without a significant breakthrough for this plant.

    Fig.1.Structures of compounds 1–3.

    Fig.2.The 1H–1H COSY (thick lines) and key HMBC correlations (pink arrows,from 1H to 13C) of compounds 1-3.

    Our research group has already reported a number of sesquiterpenes fromA.macrocephala[15].Continuing the search for structurally diverse and biologically interesting metabolites from this plant,we turned our focus toward eudesmanolide hybrids.This effort resulted in the isolation of three eudesmanolide sesquiterpene-phenol hybrids with extraordinary C–C linkage,named atramacronoids A-C (1-3).Remarkably,compounds 1-3 represent the first example of naturally occurring unusual hybrids constructed from eudesmanolide sesquiterpene and phenol,possessing pentacyclic 6/6/5/5/6 skeleton by formation of C-8-C-16 and C-7-O-C-17.Compound 2 was 18-demethyl derivative of 1,while 3 was a C-11 epimer of 1 (Fig.1).Herein,the isolation,structure elucidation,possible biosynthetic pathways of these isolates,as well as preliminary mechanism of induced apoptosis through promoting the synthesis of NE,are described.As representative pioneering works,the new linkage pattern of these compounds is not only crucial for the chemical diversity and biosynthesis of sesquiterpene hybrids,but also for the pharmacological studies on anti-cancer.

    Fig.4.The overlaid experimental ECD (full lines) and calculated ECD (dash lines)spectra of compounds 1–3.

    Fig.5.The X-ray ORTEP diagrams of 1 (left) and 3 (right).The thermal ellipsoid is scaled to the 30% probability level.

    Atramacronoid A (1) was obtained as colorless needle crystals.Its molecular formula was deduced as C22H26O4from the protonated molecular ion peak atm/z355.1900 [M+H]+(calcd.for C22H27O4,355.1904) in HRESIMS,which corresponded to 10 indices of hydrogen deficiency.The IR spectrum clearly exhibited absorption bands of hydroxyl (3421 cm–1),γ-lactone (1778 cm–1),and unsubstituted double bond (1644 cm–1) functional groups.The1H NMR data (Table S1 in Supporting information) displayed the diagnostic signals of an exocyclic double bond atδH4.86 (1H,br d,J=1.6 Hz,Ha-15) and 4.63 (1H,br d,J=1.6 Hz,Hb-15),three methyl protons atδH2.13 (3H,s,H-22),1.25 (3H,d,J=7.1 Hz,H-13) and 0.76 (3H,s,H-14),two downshielded aromatic protons atδH6.56(1H,d,J=2.5 Hz,H-19) and 6.54 (1H,d,J=2.5 Hz,H-21),indicating the existence of a 1,2,3,5-tetrasubstituted phenyl ring.In accordance with the molecular formula,analysis of the13C NMR and DEPT data (Table S1) displayed 22 carbon resonances that could be attributed to three methyl groups atδC17.0 (C-14),15.1 (C-22) and 8.2 (C-13),five aliphatic methylene groups atδC49.4 (C-9),43.0 (C-1),38.0 (C-3),26.7 (C-6) and 24.0 (C-2),one exocyclic methylene atδC107.5 (C-15),two aliphatic methines atδC45.8(C-11) and 43.6 (C-5),two aromatic methines atδC119.3 (C-19)and 108.1 (C-21),five olefinic quaternary carbons atδC153.9 (C-20),150.3 (C-4),149.0 (C-17),132.9 (C-16) and 124.0 (C-18),one aliphatic quaternary carbon atδC35.0 (C-10),one ester carbonyl group atδC177.7 (C-12),and two oxygenated quaternary carbons atδC92.2 (C-7) and 90.4 (C-8).The assignments of all hydrogen and carbon signals were further achieved by its HSQC spectrum.Further analysis of the1H-1H COSY and HMBC spectra (Fig.2) led to the elucidation of the planar structure of 1.The1H-1H COSY spectrum revealed three spin systems,including H2-1/H2-2/H2-3,H-5/H2-6 and H-11/H3-13.The three coupling networks were connected by use of HMBC correlations of H3-14/C-1,C-5,C-9,C-10;H2-15/C-3,C-4,C-5; H-5/C-7,C-14; H2-6/ C-5,C-7,C-8,C-10,C-11; H3-13/C-7,C-11,C-12; H2-9/C-1,C-7,C-8.Above evidence made for the construction of the eudesmanolide moiety.The position of the remaining methyl group was located at C-18,as confirmed by HMBC correlation from H3-22 to C-17,C-18 and C-19.Correlations from H-21 to C-16,C-17 and C-19,and from H-19 to C-17,C-18 and C-21 also resulted the assignment of substituent position of methyl on phenyl ring.In addition,key correlation from H-21 to C-8 unequivocally indicated the C–C connection between C-8 and C-16.To satisfy molecular formula of unsaturation,it was deduced that C-7 was joined with C-17 by sharing oxygen atom,forming a pentacyclic 6/6/5/5/6 skeleton.Hence,the planar structure of 1 was determined as shown in Fig.1.

    Fig.3.Main NOE correlations (pink dashed double arrows) of 1–3.

    Fig.6.The 13C NMR calculation results of two plausible stereoisomers of compound 3.(a) Linear correlation plots of calculated vs. experimental 13C NMR chemical shift values of 3a and 3b.(b) Relative errors between the calculated 13C NMR chemical shifts the recorded data and DP4+ probability analysis.

    Fig.7.(a) Effects of 1 on the growth of various cell lines (48 h),with the IC50 values ranging from 13 μmol/L to 25 μmol/L,etoposide as positive.(b) 1 induced SGC-7901 cells apoptosis detected by AO/EB staining.(c,d) Representative histograms depicting cell-cycle distribution as analyzed by flow cytometry in SGC-7901 cells treated with indicated concentrations of 1 for 24 h.Counts of G2/M phase cells increased remarkably in the treated cell in a concentration-dependent manner.(e,f) SGC-7901 cells were incubated with 1 at concentrations of 0,15,and 30 μmol/L for 24 h.Apoptosis was analyzed by annexin V-FITC/TO-PRO-3 staining.(g) NE synthesis concentration in conditioned medium treated with 1.(h) NE secretion concentration in lysate treated with 1.Values are presented as mean ± SD for three individual experiments.*P<0.05,***P<0.001,****P<0.0001 vs. control.

    The relative configuration of 1 was established by ROESY spectrum (Fig.3).The CH3-14 was arbitrarily assigned asβ-orientation.The key correlation of H3-14/H-6b indicated the junction of the eudesmane rings wastrans-fused and H-5 wasα-oriented.Meanwhile,theβ-orientation of CH3-13 was deduced from the crosspeak between H3-13 and H-6b.Furthermore,the relative configurations of the chiral centers of C-7 and C-8 were deduced because of the rigid structure of 1.Consequently,the established relative configuration of 1 was determined as shown in Fig.3.The calculated ECD curve for 1 matched well with the experimental one(Fig.4),suggesting its absolute configuration to be 5S,7S,8S,10R,11S.Subsequent X-ray diffraction using Cu Kαradiation with the Flack parameter of 0.02(7) (Fig.5) verified the planner structure as well as the absolute configuration of compound 1.

    Atramacronoid B (2) was isolated as a yellow oil and had the molecular formula C21H24O4,with 14 mass unit lower than that of 1,which was deduced from HRESIMS atm/z341.1746 [M+H]+(calcd.for C21H25O4,341.1747).The NMR spectroscopic data of 2 closely resembled those of 1 (Table S1),except for the absence of resonances for the methyl unit,which suggested that 2 was 18-demethyl derivative of 1.The deduction was verified by 2D NMR experimental data analysis (Fig.2),especially by the1H-1H COSY cross-peak of H-18/H-19 and the HMBC correlations from H-21 to C-8,C-17 and C-19,from H-19 to C-17 and C-21,and from H-18 to C-16 and C-20 as well as by the chemical shifts of these hydrogen and carbon resonances.Finally,the intact planner structure of 2 was determined.Compared with 1,similar NOE correlations(Fig.3) of H3-14/H-6b and H3-13/H-6b of 2 indicated that both compounds shared identical relative configurations.Thus,the absolute configuration of 2 was determined as 5S,7S,8S,10R,11Sby comparison of the experimentally measured ECD and theoretically calculated ECD spectra.

    Scheme 1.The plausible biosynthetic pathways of compounds 1-3.

    Atramacronoid C (3) was isolated as colorless needle crystals,and possessed the same molecular formula as 1 by the HRESIMS ions atm/z355.1900 [M+H]+(calcd.for C22H27O4,355.1904).Compound 3 was an isomer of 1,which could be preliminary concluded through analyzing detailed 1D NMR (Table S1).In ROESY spectrum of 3,the correlation between H3-14 and H-6b implied that CH3-14 and H-5 wereβ- andα-oriented,respectively.In addition,correlation of H-11 with H-6b (Fig.3) suggested that 3 was 11-epimer of 1.Taken together,the relative configuration of 3 should be fixed as 5S*,7S*,8S*,10R*,11R*.To further consolidate the above deduction,the13C NMR chemical shifts of two isomers (5S*,7S*,8S*,10R*,11R*)-3 (3a) and (5S*,7S*,8S*,10R*,11S*)-3(3b) were calculated.Comparison between the experimental and the calculated13C NMR data allowed the determination of relative configuration of 3 to be 5S*,7S*,8S*,10R*,11R*,with a DP4+probability of approximately 100% (Fig.6).Based on the agreement between the experimental and calculated ECD spectra (Fig.4),finally,the absolute configuration of 3 was assigned as 5S,7S,8S,10R,11R.After repeated recrystallization in different solvent systems,we successfully obtained a crystal of 3 at CH2Cl2-CH3CN (1:1).Single crystal X-ray diffraction (Fig.5) using Cu Kαradiation with the Flack parameter of 0.04 (8) unequivocally confirmed the absolute configuration of 3.

    To the best of our knowledge,atramacronoids A-C (1-3) are the first example of eudesmanolide sesquiterpene with phenol forming C–C bondviacyclization.The hypothetical biosynthetic pathways for 1-3 are proposed as shown in Scheme 1.Biogenetically,their biogenetic precursor is traced to be atractylolone,which is biosynthesized through mevalonate pathway and abundantly occurs in this plant.Atractylolone undergoes hydration,dehydration and oxidation to produce atractylenolide II.Afterwards,sequential oxidation and dehydration reactions to afford atractylenolide III and atractylenolide I.Atractylenolide I then yield i and ii through addition and elimination reaction,which is followed by the intermolecular addition of the C–H bond and intramolecular addition of the phenol O–H bond [16] involving the formation of C–C bond between C-8 and C-16 and C–O bond between C-7 and C-17,respectively.The cyclization of i with hydroquinone or methylhydroquinone finally give rise to compounds 2 and 1,respectively.In addition,compound 2 also can be converted to 1 by Friedel-Crafts alkylation,while ii is cyclized with methylhydroquinone to produce compound 3.

    In the bioactivity assays,compound 1 exhibited stronger growth inhibitory effects on SGC-7901 cells than other human cancer lines of A549,HCT-8,HepG2,and MCF-7 (Fig.7a),with the IC50value of 13 μmol/L.Thus,SGC-7901 cells were used for further study.Morphological analysis is one of the considerations in process of apoptosis [17].To determine whether 1 could induce cell death by apoptosis,the AO/EB straining assay was performed.As shown in Fig.7b,with increasing the concentration of 1,more apoptotic cells exhibited apoptotic characteristic such as nuclear shrinkage and chromatin condensation.

    The propidium iodide (PI) and annexin V-FITC/TO-PRO-3 double staining were applied further to examine cell cycle distribution and cell apoptosis induced by 1,respectively.Cell cycle arrest is considered a critical control point for the management of cancer cell growth [18].As shown in Figs.7c and d,1 caused G2/M cell cycle arrest in SGC-7901 cells.In the apoptosis assay (Figs.7e and f),the increase of early and late apoptosis was significantly observed in SGC-7901 cells treated with 1 when compared to the control,with the percentage running up to 59.6%,and the rate of apoptosis increased in a dose-dependent manner,indicating that compound 1 could induce apoptosis in SGC-7901 cells.Amazingly,we found the synthesis and secretion of NE increased after treating cell with 1 (Figs.7g and h).This suggested that 1 could promote inflammation.From another perspective,we preliminarily inferred 1 induced apoptosis by promoting the synthesis of NE.While in contrast to 1,compound 2 showed no cytotoxicity against SGC-7901 cells at 50 μmol/L,and 3 showed moderate cytotoxicity against SGC-7901 cells with the IC50value of 27 μmol/L.However,surprisingly,compound 2 inhibited NE synthesis (Fig.S6 in Supporting information),which further backup our aforementioned result for 1.Compound 3 could also inhibit the synthesis of NE,but the effect was weaker than 2 (Fig.S6).Basing on this,we speculated that 3 showing moderate cytotoxic activity may ascribe to another mechanism,which needed to be further researched.

    In summary,the first discovery of atramacronoids A-C(1-3),featuring unprecedented eudesmanolide sesquiterpenephenol skeleton furnished by forming an unexpected C-8-C-16 linkage,represents a milestone work after decades of the research onA.macrocephala.Predictably,the discovery of fascinating compounds 1-3 enriches the structural diversity of sesquiterpene hybrids and would attract much interest of synthetic chemists for total synthetic and biosynthetic purposes.In addition,mechanistic study revealed compound 1 showed cytotoxicity against SGC-7901 cells by inducing cell apoptosis,which might through promoting the synthesis of NE.These results could provide a new insight for further pharmacological investigation.

    Declaration of competing interest

    The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

    Acknowledgments

    This work was supported by the National Natural Science Foundation of China (No.82073992) and the CAMS Innovation Fund for Medical Sciences (CIFMS,No.2021-I2M-1-071).

    Supplementary materials

    Supplementary material associated with this article can be found,in the online version,at doi:10.1016/j.cclet.2022.107743.

    av一本久久久久| 一级毛片 在线播放| 国产免费福利视频在线观看| 日本黄色日本黄色录像| 一区福利在线观看| 老司机靠b影院| 日韩 亚洲 欧美在线| 99九九在线精品视频| 亚洲欧洲日产国产| 18禁裸乳无遮挡动漫免费视频| 视频区图区小说| 久久99一区二区三区| 精品久久久久久久毛片微露脸 | 午夜福利影视在线免费观看| 丁香六月欧美| 国产成人啪精品午夜网站| 18禁裸乳无遮挡动漫免费视频| 国产一区二区三区av在线| 中国美女看黄片| 高清黄色对白视频在线免费看| 国产高清不卡午夜福利| 看免费成人av毛片| 午夜免费观看性视频| 国产真人三级小视频在线观看| av天堂在线播放| 精品国产超薄肉色丝袜足j| 男人爽女人下面视频在线观看| 亚洲国产最新在线播放| 久久久精品94久久精品| 777米奇影视久久| 又大又黄又爽视频免费| 免费观看a级毛片全部| 最新的欧美精品一区二区| 欧美在线一区亚洲| 精品国产乱码久久久久久男人| 国产成人精品在线电影| 黄色一级大片看看| 亚洲成人国产一区在线观看 | 七月丁香在线播放| 亚洲欧美成人综合另类久久久| 欧美成狂野欧美在线观看| 国产精品国产三级专区第一集| 日韩av在线免费看完整版不卡| 欧美在线一区亚洲| 少妇裸体淫交视频免费看高清 | 亚洲视频免费观看视频| 午夜福利视频在线观看免费| 伊人久久大香线蕉亚洲五| 女人被躁到高潮嗷嗷叫费观| 曰老女人黄片| 五月天丁香电影| 夜夜骑夜夜射夜夜干| 久久精品国产综合久久久| 热re99久久国产66热| 国产高清videossex| 亚洲国产中文字幕在线视频| 777米奇影视久久| 国产亚洲欧美精品永久| 亚洲成国产人片在线观看| 爱豆传媒免费全集在线观看| 如日韩欧美国产精品一区二区三区| 中文字幕人妻丝袜制服| 一二三四社区在线视频社区8| 欧美成人精品欧美一级黄| 人妻人人澡人人爽人人| 亚洲国产精品一区三区| 中文字幕最新亚洲高清| 啦啦啦在线观看免费高清www| 色综合欧美亚洲国产小说| 少妇的丰满在线观看| av又黄又爽大尺度在线免费看| 777米奇影视久久| 又粗又硬又长又爽又黄的视频| 中文精品一卡2卡3卡4更新| 日本91视频免费播放| 中文字幕亚洲精品专区| 在线亚洲精品国产二区图片欧美| 在线亚洲精品国产二区图片欧美| 免费看av在线观看网站| 精品国产超薄肉色丝袜足j| 在线观看www视频免费| 欧美成人午夜精品| 精品福利观看| 狂野欧美激情性bbbbbb| 欧美日韩精品网址| 亚洲国产精品成人久久小说| 黄色视频在线播放观看不卡| 丝袜脚勾引网站| 亚洲午夜精品一区,二区,三区| 欧美 亚洲 国产 日韩一| 欧美人与性动交α欧美软件| 2021少妇久久久久久久久久久| 黄色视频在线播放观看不卡| 亚洲欧美一区二区三区国产| 日韩一区二区三区影片| 欧美成人午夜精品| 久久久精品区二区三区| 麻豆乱淫一区二区| 久久久久国产精品人妻一区二区| 一级a爱视频在线免费观看| 在线 av 中文字幕| 国产精品久久久久成人av| 婷婷色综合www| 一本久久精品| 久久精品亚洲熟妇少妇任你| 国产老妇伦熟女老妇高清| 一边摸一边抽搐一进一出视频| 国产精品久久久久成人av| 色婷婷久久久亚洲欧美| 日本欧美国产在线视频| 亚洲国产精品成人久久小说| 国产精品99久久99久久久不卡| 亚洲一区中文字幕在线| 五月天丁香电影| 狂野欧美激情性bbbbbb| 麻豆乱淫一区二区| 欧美 日韩 精品 国产| 欧美+亚洲+日韩+国产| 国产在线一区二区三区精| 亚洲少妇的诱惑av| 国产亚洲精品第一综合不卡| 国产xxxxx性猛交| 赤兔流量卡办理| 久久av网站| 91精品三级在线观看| 老汉色av国产亚洲站长工具| 国产精品九九99| 亚洲av电影在线进入| 国产精品av久久久久免费| 成年美女黄网站色视频大全免费| 大话2 男鬼变身卡| 色精品久久人妻99蜜桃| 免费看十八禁软件| 久久精品成人免费网站| 免费高清在线观看视频在线观看| 久久精品亚洲av国产电影网| 婷婷色综合大香蕉| 菩萨蛮人人尽说江南好唐韦庄| 成人国语在线视频| 熟女少妇亚洲综合色aaa.| 亚洲综合色网址| 青春草亚洲视频在线观看| av国产精品久久久久影院| 精品少妇内射三级| 亚洲欧美清纯卡通| 成年人午夜在线观看视频| 侵犯人妻中文字幕一二三四区| 狂野欧美激情性bbbbbb| 妹子高潮喷水视频| 午夜视频精品福利| 91成人精品电影| 亚洲精品久久成人aⅴ小说| 国产91精品成人一区二区三区 | 国产精品 欧美亚洲| 国产视频首页在线观看| 欧美日韩视频高清一区二区三区二| 日本av手机在线免费观看| 少妇猛男粗大的猛烈进出视频| 精品少妇内射三级| 亚洲自偷自拍图片 自拍| 亚洲午夜精品一区,二区,三区| 亚洲五月色婷婷综合| 国产精品久久久久久精品古装| 久久久久久人人人人人| 男人舔女人的私密视频| 精品人妻一区二区三区麻豆| 精品人妻在线不人妻| 午夜福利,免费看| 国产精品九九99| 欧美激情高清一区二区三区| 久久天躁狠狠躁夜夜2o2o | 久热爱精品视频在线9| 亚洲精品国产区一区二| 国产在线一区二区三区精| 男人添女人高潮全过程视频| 久久精品亚洲熟妇少妇任你| 一二三四在线观看免费中文在| 日韩一区二区三区影片| 午夜视频精品福利| 国产淫语在线视频| 久久av网站| 波野结衣二区三区在线| 人成视频在线观看免费观看| 日本av免费视频播放| 十分钟在线观看高清视频www| 亚洲精品国产一区二区精华液| 国产视频首页在线观看| 脱女人内裤的视频| 婷婷色综合www| 久久久久国产精品人妻一区二区| 啦啦啦啦在线视频资源| 亚洲精品国产av蜜桃| 国产真人三级小视频在线观看| 欧美人与善性xxx| 欧美激情高清一区二区三区| 亚洲精品久久久久久婷婷小说| 麻豆国产av国片精品| 亚洲免费av在线视频| 国产激情久久老熟女| 精品少妇久久久久久888优播| 精品少妇内射三级| 丝袜脚勾引网站| 热re99久久精品国产66热6| 国产高清视频在线播放一区 | 飞空精品影院首页| 亚洲第一av免费看| 91精品三级在线观看| 99国产综合亚洲精品| 色精品久久人妻99蜜桃| 99精品久久久久人妻精品| 成年女人毛片免费观看观看9 | 亚洲av欧美aⅴ国产| 亚洲人成电影免费在线| 亚洲综合色网址| 国产99久久九九免费精品| 最近手机中文字幕大全| 国产亚洲av高清不卡| 国产在线一区二区三区精| 日韩电影二区| 五月开心婷婷网| 天天操日日干夜夜撸| 免费在线观看黄色视频的| 日本猛色少妇xxxxx猛交久久| 国产1区2区3区精品| 九色亚洲精品在线播放| 午夜视频精品福利| 国产av一区二区精品久久| 大香蕉久久网| 久久毛片免费看一区二区三区| 90打野战视频偷拍视频| 国产又色又爽无遮挡免| 国产亚洲欧美在线一区二区| 国产黄色免费在线视频| 国产麻豆69| 国产人伦9x9x在线观看| 精品久久久精品久久久| 亚洲国产欧美日韩在线播放| 丁香六月天网| 蜜桃在线观看..| 免费观看人在逋| 日本色播在线视频| 国产精品免费大片| 国产免费视频播放在线视频| 97精品久久久久久久久久精品| 嫩草影视91久久| a级片在线免费高清观看视频| 亚洲成色77777| 亚洲人成电影观看| 欧美黄色淫秽网站| 亚洲精品av麻豆狂野| 女性被躁到高潮视频| 日韩制服丝袜自拍偷拍| 考比视频在线观看| 天天添夜夜摸| 国产一区二区三区av在线| 亚洲欧洲日产国产| 一级毛片我不卡| 亚洲精品在线美女| h视频一区二区三区| av有码第一页| 国产精品成人在线| 亚洲国产中文字幕在线视频| 一级毛片我不卡| 久久久久久久大尺度免费视频| 久久亚洲精品不卡| 国产av精品麻豆| 国产精品成人在线| 亚洲欧洲日产国产| 老司机亚洲免费影院| 18禁观看日本| 黄片小视频在线播放| 狠狠婷婷综合久久久久久88av| 欧美人与性动交α欧美精品济南到| 欧美日韩亚洲国产一区二区在线观看 | 日韩大片免费观看网站| 亚洲色图综合在线观看| 九色亚洲精品在线播放| 在线观看人妻少妇| www.av在线官网国产| 婷婷色麻豆天堂久久| 两个人看的免费小视频| 国产免费一区二区三区四区乱码| 亚洲精品第二区| av在线老鸭窝| 性高湖久久久久久久久免费观看| 超色免费av| 日本猛色少妇xxxxx猛交久久| 亚洲成人手机| 婷婷成人精品国产| 欧美变态另类bdsm刘玥| 美女脱内裤让男人舔精品视频| 亚洲人成电影免费在线| 91老司机精品| 少妇 在线观看| 久久亚洲精品不卡| 高清黄色对白视频在线免费看| 精品一区二区三区四区五区乱码 | 色婷婷久久久亚洲欧美| av在线app专区| 久久久久精品人妻al黑| 日韩大码丰满熟妇| 亚洲综合色网址| 99国产精品一区二区三区| 韩国精品一区二区三区| 亚洲男人天堂网一区| av网站免费在线观看视频| 各种免费的搞黄视频| 99久久99久久久精品蜜桃| 午夜精品国产一区二区电影| 国产av一区二区精品久久| 国产成人精品无人区| 国产精品人妻久久久影院| 男男h啪啪无遮挡| 在线亚洲精品国产二区图片欧美| 国产欧美日韩一区二区三 | 亚洲精品一区蜜桃| 捣出白浆h1v1| 后天国语完整版免费观看| 多毛熟女@视频| 色婷婷久久久亚洲欧美| 波多野结衣av一区二区av| 叶爱在线成人免费视频播放| 美女主播在线视频| 久久99热这里只频精品6学生| 日韩一区二区三区影片| 成年动漫av网址| 高清黄色对白视频在线免费看| 菩萨蛮人人尽说江南好唐韦庄| 日日爽夜夜爽网站| 日韩制服丝袜自拍偷拍| 性高湖久久久久久久久免费观看| 国产精品成人在线| 在线观看国产h片| 欧美成人午夜精品| 91麻豆精品激情在线观看国产 | 久久 成人 亚洲| 午夜两性在线视频| 久久久欧美国产精品| 日韩av不卡免费在线播放| 狂野欧美激情性xxxx| 亚洲欧美清纯卡通| 亚洲国产毛片av蜜桃av| 亚洲九九香蕉| 日韩一卡2卡3卡4卡2021年| 啦啦啦在线免费观看视频4| 另类精品久久| 亚洲av美国av| 超色免费av| 青青草视频在线视频观看| 建设人人有责人人尽责人人享有的| 国产又色又爽无遮挡免| 亚洲激情五月婷婷啪啪| xxx大片免费视频| 老司机影院成人| 十八禁高潮呻吟视频| 欧美激情极品国产一区二区三区| 别揉我奶头~嗯~啊~动态视频 | www.熟女人妻精品国产| 亚洲午夜精品一区,二区,三区| 国产午夜精品一二区理论片| 亚洲激情五月婷婷啪啪| 国产精品 欧美亚洲| 午夜两性在线视频| 国产一卡二卡三卡精品| 汤姆久久久久久久影院中文字幕| 国产精品一区二区在线不卡| 欧美成人午夜精品| 国产91精品成人一区二区三区 | 国语对白做爰xxxⅹ性视频网站| videos熟女内射| 丝袜美腿诱惑在线| 两人在一起打扑克的视频| 欧美 亚洲 国产 日韩一| 精品国产一区二区三区四区第35| 男女之事视频高清在线观看 | 一区二区三区四区激情视频| 国产高清视频在线播放一区 | 国产精品久久久人人做人人爽| 久久精品成人免费网站| 搡老乐熟女国产| 婷婷成人精品国产| 看十八女毛片水多多多| 亚洲伊人久久精品综合| 午夜福利影视在线免费观看| av天堂在线播放| 久久精品aⅴ一区二区三区四区| 亚洲国产精品一区二区三区在线| 日本午夜av视频| 中文字幕最新亚洲高清| 蜜桃国产av成人99| 久久鲁丝午夜福利片| 视频区图区小说| 一本综合久久免费| 国产精品香港三级国产av潘金莲 | 亚洲av片天天在线观看| 黑人巨大精品欧美一区二区蜜桃| 丝袜美腿诱惑在线| 欧美少妇被猛烈插入视频| 亚洲精品一卡2卡三卡4卡5卡 | 欧美黄色淫秽网站| 美女国产高潮福利片在线看| 日韩电影二区| 十八禁人妻一区二区| 欧美大码av| 丝袜在线中文字幕| 久久久国产精品麻豆| 桃花免费在线播放| av不卡在线播放| 精品国产一区二区三区四区第35| 十八禁人妻一区二区| 国产99久久九九免费精品| 国产亚洲av片在线观看秒播厂| 51午夜福利影视在线观看| 大片电影免费在线观看免费| 97人妻天天添夜夜摸| 久久天堂一区二区三区四区| 午夜av观看不卡| 国产成人免费无遮挡视频| 涩涩av久久男人的天堂| 欧美激情高清一区二区三区| 91麻豆av在线| 日韩 亚洲 欧美在线| 欧美激情 高清一区二区三区| 制服诱惑二区| 精品高清国产在线一区| 亚洲第一av免费看| 亚洲av国产av综合av卡| 校园人妻丝袜中文字幕| 极品少妇高潮喷水抽搐| 满18在线观看网站| 国产高清国产精品国产三级| 女人被躁到高潮嗷嗷叫费观| 香蕉丝袜av| 男女高潮啪啪啪动态图| 老司机靠b影院| 中文字幕另类日韩欧美亚洲嫩草| 国产成人啪精品午夜网站| 超碰97精品在线观看| 90打野战视频偷拍视频| 国产男人的电影天堂91| 亚洲精品第二区| 国产亚洲欧美在线一区二区| 性少妇av在线| 午夜两性在线视频| 亚洲av电影在线进入| 成人18禁高潮啪啪吃奶动态图| 久久久久久亚洲精品国产蜜桃av| 婷婷色综合www| 高清视频免费观看一区二区| 18禁裸乳无遮挡动漫免费视频| 亚洲精品成人av观看孕妇| 国产av精品麻豆| 人人澡人人妻人| 国产在线一区二区三区精| 免费看十八禁软件| 亚洲精品国产av成人精品| 尾随美女入室| 成年女人毛片免费观看观看9 | 黄片播放在线免费| 亚洲成人免费av在线播放| 欧美成狂野欧美在线观看| 久久精品亚洲熟妇少妇任你| 青春草视频在线免费观看| 你懂的网址亚洲精品在线观看| 啦啦啦在线观看免费高清www| 欧美日韩黄片免| 久久久久精品人妻al黑| 两性夫妻黄色片| 精品高清国产在线一区| videos熟女内射| 亚洲人成电影观看| 久久久久久久久免费视频了| 国产高清视频在线播放一区 | 欧美av亚洲av综合av国产av| 永久免费av网站大全| 久久国产精品人妻蜜桃| 亚洲成人免费av在线播放| 国产成人精品久久二区二区91| www.熟女人妻精品国产| 少妇粗大呻吟视频| 国产成人精品无人区| 亚洲色图综合在线观看| 午夜福利视频在线观看免费| 亚洲欧美一区二区三区黑人| 一级毛片电影观看| 亚洲精品国产区一区二| 欧美精品一区二区大全| 久久久久精品国产欧美久久久 | 大香蕉久久成人网| 看免费av毛片| 男人添女人高潮全过程视频| 国产熟女午夜一区二区三区| 国语对白做爰xxxⅹ性视频网站| 人妻 亚洲 视频| 免费高清在线观看视频在线观看| 真人做人爱边吃奶动态| 精品国产国语对白av| 欧美精品高潮呻吟av久久| 交换朋友夫妻互换小说| 中国国产av一级| 老熟女久久久| 亚洲七黄色美女视频| 亚洲欧洲精品一区二区精品久久久| 亚洲国产成人一精品久久久| 国产有黄有色有爽视频| 欧美另类一区| 999精品在线视频| 一级毛片黄色毛片免费观看视频| 伦理电影免费视频| 晚上一个人看的免费电影| 久久中文字幕一级| 七月丁香在线播放| 欧美日韩国产mv在线观看视频| 久久久久久久国产电影| 国产av精品麻豆| 老司机午夜十八禁免费视频| 美女福利国产在线| 免费少妇av软件| 国产精品av久久久久免费| 久久久久久久精品精品| 涩涩av久久男人的天堂| 久久精品亚洲av国产电影网| 老司机影院成人| 十八禁网站网址无遮挡| 一级片'在线观看视频| 日本五十路高清| 一级,二级,三级黄色视频| 久久国产亚洲av麻豆专区| 国产又色又爽无遮挡免| 亚洲天堂av无毛| 超碰成人久久| a级片在线免费高清观看视频| 香蕉国产在线看| 又黄又粗又硬又大视频| 国产不卡av网站在线观看| bbb黄色大片| 又紧又爽又黄一区二区| 狠狠婷婷综合久久久久久88av| 欧美国产精品一级二级三级| 国产爽快片一区二区三区| 亚洲一码二码三码区别大吗| 久久精品久久精品一区二区三区| 晚上一个人看的免费电影| 亚洲一区二区三区欧美精品| 色播在线永久视频| 久久亚洲精品不卡| 国产一区二区三区av在线| 欧美日韩精品网址| 欧美日韩亚洲综合一区二区三区_| 亚洲欧洲精品一区二区精品久久久| 国产在线一区二区三区精| 婷婷色麻豆天堂久久| 中文字幕av电影在线播放| 国产欧美日韩一区二区三 | 欧美亚洲日本最大视频资源| 精品久久久久久久毛片微露脸 | 久久精品aⅴ一区二区三区四区| 午夜老司机福利片| 悠悠久久av| 欧美xxⅹ黑人| av国产精品久久久久影院| 久久毛片免费看一区二区三区| 亚洲一卡2卡3卡4卡5卡精品中文| 丁香六月欧美| 精品视频人人做人人爽| 18禁裸乳无遮挡动漫免费视频| 99热全是精品| 国产女主播在线喷水免费视频网站| 国产在视频线精品| 欧美黑人欧美精品刺激| 18禁裸乳无遮挡动漫免费视频| 一级a爱视频在线免费观看| 久久中文字幕一级| 亚洲,一卡二卡三卡| 另类亚洲欧美激情| 日韩中文字幕视频在线看片| 国产精品国产三级国产专区5o| 国产精品 国内视频| 99九九在线精品视频| 老汉色av国产亚洲站长工具| 99热网站在线观看| 欧美成人午夜精品| 交换朋友夫妻互换小说| 免费在线观看视频国产中文字幕亚洲 | 女警被强在线播放| 97精品久久久久久久久久精品| www.av在线官网国产| 伦理电影免费视频| 国产爽快片一区二区三区| 69精品国产乱码久久久| 97精品久久久久久久久久精品| 香蕉丝袜av| 国产免费一区二区三区四区乱码| 日韩电影二区| 两人在一起打扑克的视频| 久久久精品区二区三区| av网站免费在线观看视频| 成年人午夜在线观看视频| 国产精品.久久久| 国产精品一区二区免费欧美 | 国产老妇伦熟女老妇高清| 天天添夜夜摸| 一区二区三区四区激情视频| 高清视频免费观看一区二区| 欧美中文综合在线视频| 涩涩av久久男人的天堂| 亚洲美女黄色视频免费看| 日韩一区二区三区影片| 丝袜人妻中文字幕| 国产老妇伦熟女老妇高清| 亚洲久久久国产精品| 欧美国产精品一级二级三级| 久久亚洲精品不卡| 欧美黄色淫秽网站| 女人被躁到高潮嗷嗷叫费观|