新型螺环吡咯酮双氧化吲哚类化合物的无催化剂合成及其抗白血病活性
|
摘要
以3-异硫氰基氧化吲哚与3-丙二腈缩合的3-烯氧化吲哚为原料,乙腈为溶剂,在无催化剂存在的条件下于室温发生[3+2]环加成反应,合成了6个新型的螺环吡咯酮双氧化吲哚类化合物(3a～3f),产率91%～95%,dr 17/1～> 20/1,其结构经1H NMR,13C NMR和HR-MS(ESI-TOF)表征。采用MTT法研究了3a～3f对人白血病细胞(K562)的体外抗肿瘤活性。结果表明:化合物3c对K562具有明显的抑制活性(IC50为36. 3μM),与阳性对照药顺铂接近。
Six novel dispiropyrrolidinyloxindoles( 3 a ～ 3 f) were synthesized via a [3 + 2]cycloaddition of 3-isothiocyanato oxindoles with isatylidene malononitriles under catalyst-free condition,by using MeCN as solvent. The yields and dr of 3 a ～ 3 f were 91% ～ 95% and 17/1 ～ > 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,using the commercially available broad-spectrum anticancer drug Cisplatin as a positive control. The results showed that 3 c exhibited well inhibition activity against K562 with IC50 of 36. 3 μM,which was similar to Cisplatin.
Six novel dispiropyrrolidinyloxindoles( 3 a ～ 3 f) were synthesized via a [3 + 2]cycloaddition of 3-isothiocyanato oxindoles with isatylidene malononitriles under catalyst-free condition,by using MeCN as solvent. The yields and dr of 3 a ～ 3 f were 91% ～ 95% and 17/1 ～ > 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,using the commercially available broad-spectrum anticancer drug Cisplatin as a positive control. The results showed that 3 c exhibited well inhibition activity against K562 with IC50 of 36. 3 μM,which was similar to Cisplatin.
引文
[1] 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.
[2] ARUN Y,BHASKAR G,BALACHANDRAN C,et al. Facile one-pot synthesis of novel dispirooxindolepyrrolidine derivatives and their antimicrobial and anticancer activity against A549 human lung adenocarcinoma cancer cell line[J]. Bioorg Med Chem Lett,2013,23:1839-1845.
[3] KIA Y,OSMAN H,KUMAR R S. Synthesis and discovery of novel piperidone-grafted mono-and bis-spirooxindole-hexahydropyrrolizines as potent cholinesterase inhibitors[J]. Bioorg Med Chem,2013,21:1696-1707.
[4] QU J,FANG L,REN X D. Bisindole alkaloids with neural anti-inflammatory activity from gelsemium elegans[J]. J Nat Prod,2013,76:2203-2209.
[5] CHEN W B,WU Z J,HU J,et al. Organocatalytic direct asymmetric Aldol reactions of 3-isothiocyanato oxindoles to ketones:stereocontrolled synthesis of spirooxindoles bearing highly congested contiguous tetrasubstituted stereocenters J]. Org Lett,2011,13:2472-2475.
[6] KATO S,YOSHINO T,SHIBASAKI M,et al. Catalytic asymmetric synthesis of spirooxindoles by a Mannich-type reaction of isothiocyanato oxindoles[J]. Angew Chem Int Ed,2012,51:7007-7010.
[7] KATO S,KANAI M,MATSUNAGA S. Catalytic asymmetric synthesis of spirooxindoles via addition of isothiocyanato oxindoles to aldehydes under dinuclear nickel schiff base catalysis[J]. Chem Asian J,2013,8:1768-1771.
[8] LIU X L,HAN W Y,ZHANG X M,et al. Highly efficient and stereocontrolled construction of 3,3'-pyrrolidonyl spirooxindoles via organocatalytic domino Michael/cyclization reaction[J]. Org Lett,2013,15:1246-1249.
[9] HAN W Y,LI S W,WU Z J,et al. 3-isothiocyanato oxindoles serving as powerful and versatile precursors to structurally diverse dispirocyclic thiopyrrolidineoxindoles through a cascade Michael/cyclization process with amino-thiocarbamate catalysts[J]. Chem Eur J,2013,19:5551-5556.
[10] 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.
[11]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.
[12]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.
[13] 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.
[2] ARUN Y,BHASKAR G,BALACHANDRAN C,et al. Facile one-pot synthesis of novel dispirooxindolepyrrolidine derivatives and their antimicrobial and anticancer activity against A549 human lung adenocarcinoma cancer cell line[J]. Bioorg Med Chem Lett,2013,23:1839-1845.
[3] KIA Y,OSMAN H,KUMAR R S. Synthesis and discovery of novel piperidone-grafted mono-and bis-spirooxindole-hexahydropyrrolizines as potent cholinesterase inhibitors[J]. Bioorg Med Chem,2013,21:1696-1707.
[4] QU J,FANG L,REN X D. Bisindole alkaloids with neural anti-inflammatory activity from gelsemium elegans[J]. J Nat Prod,2013,76:2203-2209.
[5] CHEN W B,WU Z J,HU J,et al. Organocatalytic direct asymmetric Aldol reactions of 3-isothiocyanato oxindoles to ketones:stereocontrolled synthesis of spirooxindoles bearing highly congested contiguous tetrasubstituted stereocenters J]. Org Lett,2011,13:2472-2475.
[6] KATO S,YOSHINO T,SHIBASAKI M,et al. Catalytic asymmetric synthesis of spirooxindoles by a Mannich-type reaction of isothiocyanato oxindoles[J]. Angew Chem Int Ed,2012,51:7007-7010.
[7] KATO S,KANAI M,MATSUNAGA S. Catalytic asymmetric synthesis of spirooxindoles via addition of isothiocyanato oxindoles to aldehydes under dinuclear nickel schiff base catalysis[J]. Chem Asian J,2013,8:1768-1771.
[8] LIU X L,HAN W Y,ZHANG X M,et al. Highly efficient and stereocontrolled construction of 3,3'-pyrrolidonyl spirooxindoles via organocatalytic domino Michael/cyclization reaction[J]. Org Lett,2013,15:1246-1249.
[9] HAN W Y,LI S W,WU Z J,et al. 3-isothiocyanato oxindoles serving as powerful and versatile precursors to structurally diverse dispirocyclic thiopyrrolidineoxindoles through a cascade Michael/cyclization process with amino-thiocarbamate catalysts[J]. Chem Eur J,2013,19:5551-5556.
[10] 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.
[11]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.
[12]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.
[13] 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.