新型3-五元碳环螺环氧化吲哚类化合物的合成及其抗人白血病细胞活性
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摘要
以氧化吲哚与邻芳基二甲醛为原料,经Knoevenagel缩合(或Michael,环化反应),制得7个3-五元碳环螺环氧化吲哚(4a~4c,产率67%~86%,d/r值4∶1~10∶1)和4d~4g;4d~4g与哌啶(或四氢吡咯)和多聚甲醛经胺甲基化反应,合成了4个3-五元碳环螺环氧化吲哚(5d~5g),产率55%~67%,d/r值10∶1~>20∶1,其结构经~1H NMR,~(13)C NMR和HR-MS(ESI-TOF)表征。采用MTT法研究了4a~4c和5d~5g对人白血病细胞(K562)的体外抗肿瘤活性。结果表明:4b,5d和5f对K562抑制活性较好,IC50分别为29.3μmol·L~(-1),27.4μmol·L~(-1)和34.2μmol·L~(-1),与阳性对照药顺铂(26.8μmol·L~(-1))相当。
Seven novel five-membered carbocyclic spirooxindoles(4a~4c and 4d~4g) were prepared by knoevenagel condensation(or Michael,cyclization),using oxindole and o-aryldicarboxaldehyde as the materials.The yields and d/r of 4a~4c were 67%~86% and 4∶1~10∶1,respectively.Four five-membered carbocyclic spirooxindoles(5d~5g) were synthesized by the aminomethylation reaction of 4d~4g with piperidine(or pyrrdidine) and paraformaldehyde.The yields and d/r of 5d~5g were55%~67% and 10 ∶ 1~>20∶1,respectively.The structures were characterized by1 H NMR,13 C NMR and HR-MS(ESI-TOF).The in vitro antitumor activities against human leukemia cells(K562) were demonstrated by MTT assays.The results showed that 4b,5d and 5f showed best activities equipotent than the positive control of Cisplatin(26.8 μmol·L~(-1)),with IC50 of 29.3 μmol·L-1,27.4 μmol·L~(-1) and 34.2 μmol·L~(-1),respectively.
Seven novel five-membered carbocyclic spirooxindoles(4a~4c and 4d~4g) were prepared by knoevenagel condensation(or Michael,cyclization),using oxindole and o-aryldicarboxaldehyde as the materials.The yields and d/r of 4a~4c were 67%~86% and 4∶1~10∶1,respectively.Four five-membered carbocyclic spirooxindoles(5d~5g) were synthesized by the aminomethylation reaction of 4d~4g with piperidine(or pyrrdidine) and paraformaldehyde.The yields and d/r of 5d~5g were55%~67% and 10 ∶ 1~>20∶1,respectively.The structures were characterized by1 H NMR,13 C NMR and HR-MS(ESI-TOF).The in vitro antitumor activities against human leukemia cells(K562) were demonstrated by MTT assays.The results showed that 4b,5d and 5f showed best activities equipotent than the positive control of Cisplatin(26.8 μmol·L~(-1)),with IC50 of 29.3 μmol·L-1,27.4 μmol·L~(-1) and 34.2 μmol·L~(-1),respectively.
引文
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[3]Greshock T J,Grubbs A W,Jiao P,et al.Isolation,structure elucidation,and biomimetic total synthesis of versicolamide-B,and the isolation of antipodal(+)-stephacidin-A and(+)-notoamide-B from aspergillus versicolor NRRL-35600[J].Angew Chem Int Ed,2008,47:3573-3577.
[4]Mugishima T,Tsuda M,Kasai Y,et al.Absolute stereochemistry of citrinadins A and B from marine-derived fungus[J].J Org Chem,2005,70:9430-9435.
[5]Albertshofer K,Tan B,Barbas III C F,et al.Assembly of spirooxindole derivatives containing four consecutive stereocenters via organocatalytic Michael-Henry cascade reactions[J].Org Lett,2012,14:1834-1837.
[6]Sun W,Zhu G,Hong C,et al.An organocatalytic cascade strategy for the enantioselective construction of spirocyclopentane bioxindoles containing three contiguous stereocenters and two spiro quaternary centers[J].Chem Eur J,2012,18:6737-6741.
[7]Tan B,Candeias N R,Barbas III C F,et al.Construction of bispirooxindoles containing three quaternary stereocentres in a cascade using a single multifunctional organocatalyst[J].Nat Chem,2011,3:473-477.
[8]Zhong F,Han X,Wang Y,et al.Highly enantioselective[3+2]annulation of Morita-Baylis-Hillman adducts mediated by L-threonine-derived phosphines:Synthesis of 3-spirocyclopentene-2-oxindoles having two contiguous quaternary centers[J].Angew Chem Int Ed,2011,50:7837-7841.
[9]Tan B,Candeias N R,Barbas III C F,et al.Corestructure-motivated design of a phosphine-catalyzed[3+2]cycloaddition reaction:Enantioselective syntheses of spirocyclopenteneoxindoles[J].J Am Chem Soc,2011,133:4672-4675.
[10]Deng H P,Wei Y,Shi M,et al.Highly regio-and diastereoselective construction of spirocyclopenteneoxindoles through phosphine-catalyzed[3+2]annulation of Morita-Baylis-Hillman carbonates with isatylidene malononitriles[J].Org Lett,2011,13:3348-3351.
[11]Voituriez A,Pinto N,Neel M,et al.An organocatalytic[3+2]cyclisation strategy for the highly enantioselective synthesis of spirooxindoles authors[J].Chem Eur J,2010,16:12541-12544.
[12]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.
[13]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.
[14]杨超,杨俊,郭丰敏,等.新型芝麻酚并吡喃螺环氧化吲哚拼接衍生物的合成[J].合成化学,2015,23(7):599-602.
[15]Mosman T J.Rapid colorimetric assay for eellulair growth and survival:Application and cytotxicity assays[J].Immunol Methods,1983,65:55-63.
[16]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.