基于姜黄酮骨架的新型螺环氧化吲哚类化合物的合成及其抗癌活性
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摘要
以取代靛红、芳姜二烯酮与α-氨基苯乙酸为原料,在甲苯中回流,经1,3-偶极子3+2环加成反应合成了3个新型的基于姜黄酮骨架螺环氧化吲哚类化合物(3a～3c),收率65%～73%,dr值10/1～15/1,其结构经~1H NMR,~(13)C NMR和HR-MS(ESI-TOF)表征,相对构型经3c的单晶结构确定。采用MTT法研究了3a～3c对人白血病细胞(K562)、人肺癌细胞(A549)和人前列腺癌(PC-3)的体外抗肿瘤活性。结果表明:化合物3b对K562具有明显的抑制活性(IC_(50)为37. 5μM),接近于阳性对照药顺铂。
Three novel turmerone-spiropyrrolidinyloxindoles( 3a ～ 3c) were synthesized via a multicomponent 1,3-dipolar cycloaddition event of dienones with azomethine ylides( thermally generated in situ from isatins and alpha-aminophenylacetic acid). The yields and dr were 65% ～ 73% and 10/1 ～15/1,respectively. The structures were characterized by ~1H NMR,~(13)C NMR and HR-MS( ESI-TOF).The relative configuration were further confirmed by X-ray crystallographic studies of single crystal of 3 c. The in vitro antitumor activities against human leukemia cells( K562),human lung cancer cell( A549) and human prostate cancer( PC-3) were demonstrated by MTT assays. The results showed that 3 b exhibited well inhibition activities against K562 with IC5037. 5 μM,and showed equipotent potent than the positive control of Cisplatin.
Three novel turmerone-spiropyrrolidinyloxindoles( 3a ～ 3c) were synthesized via a multicomponent 1,3-dipolar cycloaddition event of dienones with azomethine ylides( thermally generated in situ from isatins and alpha-aminophenylacetic acid). The yields and dr were 65% ～ 73% and 10/1 ～15/1,respectively. The structures were characterized by ~1H NMR,~(13)C NMR and HR-MS( ESI-TOF).The relative configuration were further confirmed by X-ray crystallographic studies of single crystal of 3 c. The in vitro antitumor activities against human leukemia cells( K562),human lung cancer cell( A549) and human prostate cancer( PC-3) were demonstrated by MTT assays. The results showed that 3 b exhibited well inhibition activities against K562 with IC5037. 5 μM,and showed equipotent potent than the positive control of Cisplatin.
引文
[1] GALLIFORD C V,SCHEIDT K A. Pyrrolidinyl-spirooxindole natural products as inspirations for the development of potential therapeutic agents[J]. Angew Chem Int Ed,2007,46:8748-8758.
[2] HAN W Y,ZHAO J Q,ZUO J,et al. Recent advances of a-isothiocyanato compounds in the catalytic asymmetric reaction[J]. Adv Synth Catal,2015,357:3007-3031.
[3] CUI C B,KAKEYA H,OSADA H,et al. Novel mammalian cell cycle inhibitors,spirotryprostatins A and B,produced by Aspergillus fumigatus,which inhibit mammalian cell cycle at G2/M phase[J]. Tetrahedron1996,52:12651-12666.
[4] DING K,LU Y,COLESKA N Z,et al. Structurebased design of potent non-peptide MDM2 inhibitors[J]. J Am Chem Soc,2005,127:10130-10131.
[5] CALIXTO J B,OTUKI M F,SANTOS A R S. Antiinflammatory compounds of plant origin. Part I. action on arachidonic acid pathway,nitric oxide and nuclear factorκB(NF-κB)[J]. Planta Med,2003,69:973-983.
[6] HONG C H,NOH M S,LEE W Y,et al. Inhibitory effects of natural sesquiterpenoids isolated from the rhizomes of Curcuma zedoaria on prostaglandin E2 and nitric oxide production[J]. Planta Med,2002,68:545-547.
[7] MOTOYOSHIYA J,MIYAJIMA M,HIRAKAWA K,et al. Dimethyl(2-oxo-4-methyl-3-pentenyl)phosphonate as a precursor of alpha,alpha'-dienones. Short syntheses of(.+-.)-alpha-atlantone and(.+-.)-ar-turmerone[J]. J Org Chem,1985,50:1326-1327.
[8] PRETE D D,MILLAN E,POLLASTRO F,et al.Turmeric sesquiterpenoids:Expeditious resolution,comparative bioactivity,and a new bicyclic turmeronoid[J]. Journal of Natural Products,2016,79:267-273.
[9] ALLEY M C,SCUDIERO D A,MONKS A,et al.Feasibility of drug screening with panals of human tumor cell lines using a mycroculture tetrazolium assay[J]. Cancer Res,1988,48:589-601.
[10]刘雄伟,周根,姚震,等.异噁唑拼接吡咯螺环氧化吲哚化合物的合成及其抗肿瘤活性[J].合成化学,2016,24(5):389-392.
[11]彭礼军,周根,韩朔楠,等.新型芳姜黄酮拼合吡咯螺环氧化吲哚类化合物的合成及其抗肿瘤活性[J].合成化学,2016,24(8):669-672.
[12] CCDC 1855956(3c),单晶数据可以通过剑桥晶体数据中心(www. ccdc. cam. ac. uk)免费获取.
[2] HAN W Y,ZHAO J Q,ZUO J,et al. Recent advances of a-isothiocyanato compounds in the catalytic asymmetric reaction[J]. Adv Synth Catal,2015,357:3007-3031.
[3] CUI C B,KAKEYA H,OSADA H,et al. Novel mammalian cell cycle inhibitors,spirotryprostatins A and B,produced by Aspergillus fumigatus,which inhibit mammalian cell cycle at G2/M phase[J]. Tetrahedron1996,52:12651-12666.
[4] DING K,LU Y,COLESKA N Z,et al. Structurebased design of potent non-peptide MDM2 inhibitors[J]. J Am Chem Soc,2005,127:10130-10131.
[5] CALIXTO J B,OTUKI M F,SANTOS A R S. Antiinflammatory compounds of plant origin. Part I. action on arachidonic acid pathway,nitric oxide and nuclear factorκB(NF-κB)[J]. Planta Med,2003,69:973-983.
[6] HONG C H,NOH M S,LEE W Y,et al. Inhibitory effects of natural sesquiterpenoids isolated from the rhizomes of Curcuma zedoaria on prostaglandin E2 and nitric oxide production[J]. Planta Med,2002,68:545-547.
[7] MOTOYOSHIYA J,MIYAJIMA M,HIRAKAWA K,et al. Dimethyl(2-oxo-4-methyl-3-pentenyl)phosphonate as a precursor of alpha,alpha'-dienones. Short syntheses of(.+-.)-alpha-atlantone and(.+-.)-ar-turmerone[J]. J Org Chem,1985,50:1326-1327.
[8] PRETE D D,MILLAN E,POLLASTRO F,et al.Turmeric sesquiterpenoids:Expeditious resolution,comparative bioactivity,and a new bicyclic turmeronoid[J]. Journal of Natural Products,2016,79:267-273.
[9] ALLEY M C,SCUDIERO D A,MONKS A,et al.Feasibility of drug screening with panals of human tumor cell lines using a mycroculture tetrazolium assay[J]. Cancer Res,1988,48:589-601.
[10]刘雄伟,周根,姚震,等.异噁唑拼接吡咯螺环氧化吲哚化合物的合成及其抗肿瘤活性[J].合成化学,2016,24(5):389-392.
[11]彭礼军,周根,韩朔楠,等.新型芳姜黄酮拼合吡咯螺环氧化吲哚类化合物的合成及其抗肿瘤活性[J].合成化学,2016,24(8):669-672.
[12] CCDC 1855956(3c),单晶数据可以通过剑桥晶体数据中心(www. ccdc. cam. ac. uk)免费获取.