异长叶烷基-喹唑啉-2-胺衍生物的合成与生物活性评价
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摘要
以异长叶烷酮为原料,经缩合、环化等反应合成出6个喹唑啉-2-胺衍生物(Ⅲa～Ⅲf)。采用1HNMR、13CNMR、IR、HRMS等对其结构进行了表征。采用MTT法考察了化合物Ⅲa～Ⅲf对人肝癌细胞(Hep G2)和人脐静脉内皮细胞(HUVECs)的抑制活性。结果表明:化合物Ⅲa、Ⅲb、Ⅲd、Ⅲf[半抑制浓度(IC50)分别为8.58±0.5、44.52±0.9、57.18±0.8、32.83±0.6μmol/L]对Hep G2有一定的抗肿瘤活性。其中,4-(4?-氯苯基)-6,6,10,10-四甲基-5,6,6a,7,8,9,10,10a-八氢-6a,9-甲基苯并[h]喹唑啉-2-胺(Ⅲa)抗HepG2的活性最强;只有4-[4?–(二甲基氨基)苯基]-6,6,10,10-四甲基-5,6,6a,7,8,9,10,10a-八氢-6a,9-甲基苯并[h]喹唑啉-2-胺(Ⅲf)对HUVECs有抑制活性。同时,采用叶浸渍法考察了化合物Ⅲa～Ⅲf对桃蚜的杀虫活性,结果表明,化合物Ⅲa、Ⅲd[致死中浓度(LC50)=41.0073,37.4589 mg/L]对桃蚜具有较好的杀虫活性。
A series of quinazolin-2-amine derivatives(Ⅲa～Ⅲf) were synthesized by condensation, cyclization and so on from isolongifolanone and characterized by 1HNMR, 13 CNMR, IR and HRMS. Their inhibitory activity against human hepatoma cell(HepG2) and human umbilical vein endothelial cells(HUVECs) were evaluated by MTT assay. The results showed that the half maximal inhibitory concentrations of compounds Ⅲa, Ⅲb, Ⅲd and Ⅲf were 8.58±0.5, 44.52±0.9, 57.18±0.8 and 32.83±0.6 μmol/L, indicating that these compounds showed moderate antitumor activity against HepG2. Among these compounds, compound Ⅲa, 4-(4￠-chlorophenyl)-6,6,10,10-tetramethyl-5,6,6a,7,8,9,10,10a-octahydro-6a, 9-methanobenzo[h]quinazolin-2-amine, had the best activity against HepG2. Only 4-(4'-(N,N-dimethylamino) phenyl)-6,6,10,10-tetramethyl-5,6,6a,7,8,9,10,10a-octahydro-6a,9-methanobenzo[h]quinazolin-2-amine(Ⅲf) showed a certain inhibitory activity against HUVECs. These compounds were also carried out to evaluate against Myzus persicae by a leaf-dipping method. It was found that compounds Ⅲa and Ⅲd gave excellent insecticidal activity against myzus persicae with corresponding lethal concentration(LC50) of 41.0073 and 37.4589 mg/L.
A series of quinazolin-2-amine derivatives(Ⅲa～Ⅲf) were synthesized by condensation, cyclization and so on from isolongifolanone and characterized by 1HNMR, 13 CNMR, IR and HRMS. Their inhibitory activity against human hepatoma cell(HepG2) and human umbilical vein endothelial cells(HUVECs) were evaluated by MTT assay. The results showed that the half maximal inhibitory concentrations of compounds Ⅲa, Ⅲb, Ⅲd and Ⅲf were 8.58±0.5, 44.52±0.9, 57.18±0.8 and 32.83±0.6 μmol/L, indicating that these compounds showed moderate antitumor activity against HepG2. Among these compounds, compound Ⅲa, 4-(4￠-chlorophenyl)-6,6,10,10-tetramethyl-5,6,6a,7,8,9,10,10a-octahydro-6a, 9-methanobenzo[h]quinazolin-2-amine, had the best activity against HepG2. Only 4-(4'-(N,N-dimethylamino) phenyl)-6,6,10,10-tetramethyl-5,6,6a,7,8,9,10,10a-octahydro-6a,9-methanobenzo[h]quinazolin-2-amine(Ⅲf) showed a certain inhibitory activity against HUVECs. These compounds were also carried out to evaluate against Myzus persicae by a leaf-dipping method. It was found that compounds Ⅲa and Ⅲd gave excellent insecticidal activity against myzus persicae with corresponding lethal concentration(LC50) of 41.0073 and 37.4589 mg/L.
引文
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[16]Rui Jian(芮坚), Zhang Qi(张齐), Wang Xin(王欣), et al. Synthesis andbiologicalactivityofnovelpinanylpyrazoleacetamide derivatives[J].ChineseJournalofOrganicChemistry(有机化学),2017, 37(1):218-225.
[17]Rui Jian(芮坚), Xu Xu(徐徐), Yang Yiqin(杨益琴), et al. Synthesis of a novel quinazoline derivative from isolongifolanone[J]. Chemistry andIndustryofForestProducts(林产化学与工业),2016,36(4):121-127.
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[3]Beaulieu P L, Coulombe R, Duan J, et al. Structure-based design of novelHCVNS5Bthumbpocket2allostericinhibitorswith submicromolargt1repliconpotency:discoveryofaquinazolinone chemotype[J].BioorganicandMedicinalChemistryLetters,2013,23(14):4132-4140.
[4]Sahoo B M, Dinda S C, Ravi Kumar B V, et al. Green Synthesis and evaluation of 3-(aryl)-2-thioxo-2,3-dihydro-quinazolin-4(1H)-ones as novel anticonvulsant drugs[J]. International Journal of Nanotechnology,2013, 6:2046-2052.
[5]Wang X, Li P, Li Z N, et al. Synthesis and bioactivity evaluation of novelaryliminescontaininga3-aminoethyl-2-[(p-trifluoromethoxy)anilino]-4(3H)-quinazolinone moiety[J]. Journal of Agricultural and Food Chemistry, 2013, 61(40):9575-9582.
[6]Ou Junjun(欧俊军), Liu Kechang(刘克昌), Wang Yi(王毅), et al.Synthesisandbioactivitystudiesof2,3-disubstitutedquinazolin-4(3H)-one[J].ChineseJournalofOrganicChemistry(有机化学),2013, 34(3):526-536.
[7]Drew L, Engelman J, Katayama R, et al. Concurrent roles for IGF1R and EGFR in driving acquired resistance to crizotinib and ability to overcome with a combination of the ALK/IGF1R inhibitor AZD3463and Iressa[J]. Cancer Research, 2013, 73(8 Supplement):4465.
[8]AberaM,SordellaR,KazanietzM.PKCalphaisimplicatedin epithelialtomesenchymaltransitionanderlotinibresistancein non-small cell lung carcinoma cells[J]. Cancer Research, 2013, 73(8Supplement):5261.
[9]Noolvi M N, Patel H M, Bhardwaj V, et al. Synthesis and in vitro antitumoractivityofsubstitutedquinazolineandquinoxaline derivatives:searchforanticanceragent[J].EuropeanJournalof Medicinal Chemistry, 2011, 46(6):2327-2346.
[10]WangDW,LinHY,CaoRJ,etal.Synthesisandherbicidal evaluation of triketone-containing quinazoline-2, 4-diones[J]. Journal of Agricultural and Food Chemistry, 2014, 62(49):11786-11796.
[11]Wu J, Bai S, Yue M, et al. Synthesis and insecticidal activity of 6,8-dichloro-quinazolinederivativescontainingasulfidesubstructure[J].Chemical Papers, 2014, 68(7):969-975.
[12]Gao Xingwen(高兴文), Cai Xuejian(蔡学建), Yan Kai(严凯), et al.Synthesisandanti-tobaccomosaicvirusactivityof4(3H)-quinazolinone Schiff base[J]. Chinese Journal of Organic Chemistry(有机化学), 2008, 28(10):1785-1791.
[13]Wang D W, Lin H Y, Cao R J, et al. Design, synthesis and herbicidal activity of novel quinazoline-2,4-diones as 4-hydroxyphenylpyruvate dioxygenaseinhibitors[J].PestManagementScience,2015,71(8):1122-1132.
[14]Bai Yang(白杨), Liu Liujun(刘六军), Zhou Tiaotiao(周调调), et al.The research of isolongifolanone synthesized from longifolene[J]. Fine and Specialty Chemicals(精细与专用化学品), 2011, 19(2):47-51.
[15]Rui Jian(芮坚), Yang Jinlai(杨金来), Huang Jianfeng(黄建峰), et al.Synthesis,antitumorandanti-inflammatoryactivitiesof isolongifolanonyl pyrazole derivatives[J]. Chinese Journal of Organic Chemistry(有机化学), 2016, 36(9):2183-2190.
[16]Rui Jian(芮坚), Zhang Qi(张齐), Wang Xin(王欣), et al. Synthesis andbiologicalactivityofnovelpinanylpyrazoleacetamide derivatives[J].ChineseJournalofOrganicChemistry(有机化学),2017, 37(1):218-225.
[17]Rui Jian(芮坚), Xu Xu(徐徐), Yang Yiqin(杨益琴), et al. Synthesis of a novel quinazoline derivative from isolongifolanone[J]. Chemistry andIndustryofForestProducts(林产化学与工业),2016,36(4):121-127.