色胺酮及其衍生物的合成工艺及抑制肿瘤细胞增殖的研究
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摘要
对色胺酮的合成工艺进行较为深入的研究,得出最佳合成工艺条件:以吲哚醌和靛红酸酐为原料,在三乙胺作用下,在氯仿中回流3.0 h,乙醇洗涤3次,得到色胺酮纯品.此方法产率高(93.1%),产品纯度好(99.9%),后处理方便.用此方法合成出了14个色胺酮衍生物,5个未见报道。采用MTT法检测合成的色胺酮衍生物对A549,HCT116及PC12肿瘤细胞增殖的影响,结果发现所合成的化合物对3种肿瘤细胞均有较好的抑制增值的作用。其中,8-硝基色胺酮和8,7/9-二氯色胺酮对A549具有较好的抑制活性IC_(50)分别为:1.35,0.99μmol/L,表明此类化合物具有潜在的抗肿瘤活性。
An efficient economic process for preparation of tryptanthrin has been developed by employing Et_3N as a base in CHCl_3 refluxing 3.0 h from isatoic anhydride and isatin in yield of 93.1 %, and the product purity is high(99.9%), post-treatment is convenient. Fourteen tryptanthrin derivatives(tryptanthrins) were synthesized by this method, and five of them were not reported. Inhibitory effect of synthetic tryptanthrins on the proliferation of A549, HCT116 and PC12 tumor cells was detected by MTT assay. Among the synthesized derivatives, the 8-NO_2 tryptanthrin and 8,9-2 Cl tryptanthrin displayed potent antiproliferative activity against A549 with IC_(50) values of 1.35 μmol/L and 0.99 μmol/L, indicating that these compounds have potential antitumor activity.
An efficient economic process for preparation of tryptanthrin has been developed by employing Et_3N as a base in CHCl_3 refluxing 3.0 h from isatoic anhydride and isatin in yield of 93.1 %, and the product purity is high(99.9%), post-treatment is convenient. Fourteen tryptanthrin derivatives(tryptanthrins) were synthesized by this method, and five of them were not reported. Inhibitory effect of synthetic tryptanthrins on the proliferation of A549, HCT116 and PC12 tumor cells was detected by MTT assay. Among the synthesized derivatives, the 8-NO_2 tryptanthrin and 8,9-2 Cl tryptanthrin displayed potent antiproliferative activity against A549 with IC_(50) values of 1.35 μmol/L and 0.99 μmol/L, indicating that these compounds have potential antitumor activity.
引文
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[14] LIANG Y W,WANG X N,FANG H L,et al.A highly selective and sensitive colorimetric probe for Cu2+ determination in aqueous media based on derivative of tryptanthrin[J].Analytical Sciences,2018,34(10):1111-1115.
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[22] WANG C,ZHANG L,REN A,et al.Cu-catalyzed synthesis of tryptanthrin derivatives from substituted indoles[J].Org Lett,2013,15(12):2982-2985.
[23] LEE E S,PARK J G,JAHNG Y.A facile synthesis of simple alkaloids-synthesis of 2,3-polymethylene-4(3H)-quinazolinones and related alkaloids[J].Tetrahedron Lett,2003,44(9):1883-1886.
[24] 王翠玲,刘建利,张楠楠,等.色胺酮在菘蓝中的分布、生物合成及仿生合成研究[C]//2006第六届中国药学会学术年会论文集.广州,2006.
[25] COPPOLA G M.The chemistry of isatoic anhydride[J].Synthesis,1980,7:505-536.
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[27] 黄新炜,王征,陈巧利,等.橙酮衍生物的合成及初步抗肿瘤活性研究[J].有机化学,2013,33(12):2565-2571.
[28] WANG ZH,WANG C L,SUN Y N,et al.A novel strategy to the synthesis of 4-anilinoquinazoline derivatives[J].Tetrahedron,2014,70:906-913.
[2] JAO C W,LIN W C,WU Y T,et al.Isolation,structure elucidation,and synthesis of cytotoxic tryptanthrin analogues from phaius mishmensis[J].J Nat Prod,2008,71(7):1275-1279.
[3] HENNING D,DIETMAR B,MATTHIAS H.Quantitative determination of the dual COX-2/5-LOX inhibitor tryptanthrin in Isatis tinctoria by ESI-LC-MS[J].Planta Med,2002,68(2):152-157.
[4] ZHANG S N,QI F F,FANG X,et al.Tryptophan 2,3-dioxygenase inhibitory activities of tryptanthrin derivatives[J].J Med Chem,2018,160:133-145.
[5] KIMA W,YOUNB H,KWONA T,et al.PIM1 kinase inhibitors induce radiosensitization in non-small cell lung cancer cells[J].Pharmacol Res,2013,70(1):90-101.
[6] SCHEPETKIN I A,KHLEBNIKOV A I,POTAPOV A S,et al.Synthesis,biological evaluation,and molecular modeling of 11H-indeno[1,2-b]quinoxalin-11-one derivatives and tryptanthrin-6-oxime as c-Jun N-terminal kinase inhibitors[J].J Med Chem,2019,161:179-191.
[7] PERGOLA C,JAZZAR B,ROSSI A,et al.On the inhibition of 5-lipoxygenase product formation by tryptanthrin:mechanistic studies and efficacy in vivo[J].J Pharmacol,2012,165(3):765-776.
[8] WANG Z,WU X,WANG C L,et al.Tryptanthrin protects mice against dextran sulfate sodium-induced colitis through inhibition of TNF-α/NF-κB and IL-6/STAT3 pathways[J].Molecules,2018,23(5):1062-1075.
[9] TAKEL Y,KUNIKATA T,AGA M,et al.Tryptanthrin inhibits interferon-γ-production by Peyer′s patch lymphocytes derived from mice that had been orally administered staphylococcal enterotoxin[J].J Biol Pharm Bull,2003,26(3):365-367.
[10] HWANG J M,OH T,KANEKO T,et al.Design,synthesis,and structure-activity relationship studies of tryptanthrins as antitubercular agents[J].J Nat,2013,76(3):354-367.
[11] BHATTACHARJEE A K,HARTELL M G,NICHOLS D A,et al.Structure-activity relationship study of antimalarial indolo [2,1-b]quinazoline-6,12-diones (tryptanthris).Three dimensional pharmacophore modeling and identification of new antimalarial candidates[J].Eur J Pharmacol,2004,39(1):59-67.
[12] YANG SH SH,LI X H,HU F F,et al.Discovery of tryptanthrin derivatives as potent inhibitors of indoleamine 2,3-dioxygenase with therapeutic activity in Lewis Lung Cancer (LLC) tumor-bearing mice[J].J Med Chem,2013,56:8321-8331.
[13] 王庆国,李丹,鹿宁,等.基于色胺酮衍生物的阴离子探针和分子逻辑门[J].高等学校化学学报,2014,35(10):2114-2118.
[14] LIANG Y W,WANG X N,FANG H L,et al.A highly selective and sensitive colorimetric probe for Cu2+ determination in aqueous media based on derivative of tryptanthrin[J].Analytical Sciences,2018,34(10):1111-1115.
[15] MIAO S,SHI X P,ZHANG H,et al.Proliferation-attenuating and apoptosis-inducing effects of tryptanthrin on human chronic myeloid leukemia K562 cell line in vitro[J].Molecular Sciences,2011,12:3831-3845.
[16] BERGMAN J,LINDSTR?M J O,TILSTAM U.The structure and properties of some indolic constituents in Couroupita guianensis aubl[J].Tetrahedron,1985,41(14):2879-2881.
[17] KUMAR A,TRIPATHI V D,KUMAR P.β-Cyclodextrin catalysed synthesis of tryptanthrin in water[J].Green Chemistry,2011,13:51-54.
[18] WILLIAM R B,BAKER W R,LESTER A M.Indolo[2,1-b]quinazoline-6,12-dione antibacterial compounds and methods of use thereof:US,5 441 955 [P].1995-08-15.
[19] 王翠玲,刘建利,沈小莉.天然产物色胺酮及其衍生物合成的研究进展[J].化学通报,2007,2:89-95.
[20] JAHNG Y.Progress in the studies on tryptanthrin,an alkaloid of history[J].Arch Pharm Res,2013,36:517-535.
[21] 王翠玲,侯宝龙,张宁,等.天然产物色胺酮色胺酮及其衍生物的仿生合成[J].高等化学学报,2015,36(2):274-278.
[22] WANG C,ZHANG L,REN A,et al.Cu-catalyzed synthesis of tryptanthrin derivatives from substituted indoles[J].Org Lett,2013,15(12):2982-2985.
[23] LEE E S,PARK J G,JAHNG Y.A facile synthesis of simple alkaloids-synthesis of 2,3-polymethylene-4(3H)-quinazolinones and related alkaloids[J].Tetrahedron Lett,2003,44(9):1883-1886.
[24] 王翠玲,刘建利,张楠楠,等.色胺酮在菘蓝中的分布、生物合成及仿生合成研究[C]//2006第六届中国药学会学术年会论文集.广州,2006.
[25] COPPOLA G M.The chemistry of isatoic anhydride[J].Synthesis,1980,7:505-536.
[26] 王翠玲,刘竹兰,侯宝龙,等.天然产物吲哚醌及其衍生物的合成[J].西北大学学报(自然科学版),2011,41(5):817-820.
[27] 黄新炜,王征,陈巧利,等.橙酮衍生物的合成及初步抗肿瘤活性研究[J].有机化学,2013,33(12):2565-2571.
[28] WANG ZH,WANG C L,SUN Y N,et al.A novel strategy to the synthesis of 4-anilinoquinazoline derivatives[J].Tetrahedron,2014,70:906-913.