6-取代-1-((1-取代苯基-1,2,3-三唑-4-基)甲基)-4-羰基喹啉-3-甲酸乙酯的合成表征及抗肿瘤活性
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摘要
目的:为了寻找新型抗肿瘤活性优良的先导化合物,依据喹诺酮及1,2,3-三唑类化合物抗肿瘤特性,设计7个新的6-取代-1-((1-取代苯基-1,2,3-三唑-4-基)甲基)-4-羰基喹啉-3-甲酸乙酯类化合物进行合成、体外抗肿瘤活性评价及初步构效关系研究。方法:以取代苯胺为原料,与乙氧亚甲基丙二酸二乙酯缩合,Gould-Jacobs环合制得6-取代-4-羰基喹啉-3-甲酸乙酯;取代苯基叠氮与溴丙炔经点击化学(click chemistry)制得4-溴甲基-1-取代苯基-1,2,3-三唑;6-取代-4-羰基喹啉-3-甲酸乙酯与4-溴甲基-1-取代苯基-1,2,3-三唑经N烷基化反应制得目标化合物。化合物结构经IR,1H-NMR,元素分析证实,MTT法测目标化合物体外抗肿瘤活性。结果:化合物表现出不同程度抗肿瘤活性。化合物4c,4e对Hep G2,HT29的IC50接近或高于对照药物DDP,尤其对人白血病细胞株HL60具有很强抑制增殖作用,活性高于DDP,IC50分别为15.03,13.32μmol·L-1。结论:初步构效关系研究表明,标题化合物6位及1位上苯基三唑的苯环对位都被Cl,F等卤素原子取代的6-取代-1-((1-取代苯基-1,2,3-三唑-4-基)甲基)-4-羰基喹啉-3-甲酸乙酯对Hep G2,HT29和HL60具有抗肿瘤活性。
Objective: To find novel lead compounds with promising antitumor activity through designing and synthesizing a series of novel ethyl 6-substituted-1-((1-(4-substituted phenyl)-1,2,3-triazol-4-yl) methyl)-4-oxoquinoline-3-carboxylate derivatives based on the antitumor characteristics of quinolones and 1,2,3-triazol derivatives. Methods: Title compounds were synthesized through Gould-Jacobs reaction,click chemistry,and alkylation.The structures of the title compounds were confirmed by1H-NMR,IR,and elemental analysis. The compounds were evaluated for antitumor activity against five selected human tumor cell lines of Hep G2,A549,Hela,HT29,and HL60 by MTT assay. Results: The title compounds exhibited moderate to potent antitumor activity. Among them,several compounds displayed excellent antitumor activities against Hep G2,HT29,and HL60. Particularly,compounds 4 c and 4 e were more potent than DDP against HL60 with IC50 values of 15. 03 and 13. 32 μmol·L- 1.Conclusions: The analysis of structure-activity relationship showed that the title compounds which were substitutedby Cl or F at positions 1 and benzene of 6 were a kind of promising antitumor compounds against Hep G2,HT29,and HL60.
Objective: To find novel lead compounds with promising antitumor activity through designing and synthesizing a series of novel ethyl 6-substituted-1-((1-(4-substituted phenyl)-1,2,3-triazol-4-yl) methyl)-4-oxoquinoline-3-carboxylate derivatives based on the antitumor characteristics of quinolones and 1,2,3-triazol derivatives. Methods: Title compounds were synthesized through Gould-Jacobs reaction,click chemistry,and alkylation.The structures of the title compounds were confirmed by1H-NMR,IR,and elemental analysis. The compounds were evaluated for antitumor activity against five selected human tumor cell lines of Hep G2,A549,Hela,HT29,and HL60 by MTT assay. Results: The title compounds exhibited moderate to potent antitumor activity. Among them,several compounds displayed excellent antitumor activities against Hep G2,HT29,and HL60. Particularly,compounds 4 c and 4 e were more potent than DDP against HL60 with IC50 values of 15. 03 and 13. 32 μmol·L- 1.Conclusions: The analysis of structure-activity relationship showed that the title compounds which were substitutedby Cl or F at positions 1 and benzene of 6 were a kind of promising antitumor compounds against Hep G2,HT29,and HL60.
引文
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[17]TSUZUKI Y,TOMITA K,SHIBAMORI K,et al.Synthesis and structure-activity relationships of novel 7-substituted 1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acids as antitumor agents.Part 2[J].J Med Chem,2004,47(8):2097-2109.
[18]TOMITA K,TSUZUKI Y,SHIBAMORI K,et al.Synthesis and structure-activity relationships of novel 7-substituted 1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acids as antitumor agents.Part 1[J].J Med Chem,2002,45(25):5564-5575.
[19]BOTEVA AA,KRASNYKH OP.The methods of synthesis,modification,and biological activity of 4-quinolones[J].Chem Heterocycl com+,2009,45(7):757-785.
[20]LI XL,LIN YJ,YUAN YK,et al.Novel efficient anticancer agents and DNA-intercalators of 1,2,3-triazol-1,8-naphthalimides:design,synthesis,and biological activity[J].Tetrahedron,2011,67(12):2299-2304.
[2]AL-TRAWNEH SA,ZAHRA JA,KAMAL MR,et al.Synthesis and biological evaluation of tetracyclic fluoroquinolones as antibacterial and anticancer agents[J].Bioorg Med Chem,2010,18(16):5873-5884.
[3]BERTOSA B,ALEKSIC M,KARMINISKI-ZAMOLA G,et al.QSAR analysis of antitumor active amides and quinolones from thiophene series[J].Int J Pharm,2010,394(1-2):106-114.
[4]KHAN IA,SIDDIQUI S,REHMANI S,et al.Fluoroquinolones inhibit HCV by targeting its helicase[J].Antivir Ther,2012,17(3):467-476.
[5]DANESHTALABA M,AHMEDA A.Nonclassical Biological Activities of Quinolone Derivatives[J].J Pharm Pharm Sci,2012,15(1):52-72.
[6]PARK CH,LEE J,JUNG HY,et al.Identification,biological activity,and mechanism of the anti-ischemic quinolone analog[J].Bioorg Med Chem,2007,15(20),6517-6526.
[7]ZHOU FW,LEI HS,FAN L,et al.Design,synthesis,and biological evaluation of dihydroartemisinin-fluoroquinolone conjugates as a novel type of potential antitubercula agents[J].Bioorg Med Chem Lett,2014,24(8):1912-1917.
[8]YOU QD,LI ZY,HUANG CH.Discovery of a novel series of quinolone and naphthyridine derivatives as potential topoisomerase I inhibitors by scaffold modification[J].J Med Chem,2009,52(18):5649-5661.
[9]CHANG YH,HSU MH,WANG SH,et al.Design and synthesis of 2-(3-benzo[b]thienyl)-6,7-methylenedioxyquinolin-4-one analogues as potent antitumor agents that inhibit tubulin assembly[J].J Med Chem,2009,52(15),4883-4891.
[10]MARTIC S,TACKENBURG S,BILOKIN Y.Electrochemical screening of the indole/quinolone derivatives as potential protein kinase CK2 inhibitors[J].Anal Biochem,2012,421(2):617-621.
[11]赵芡,卢俊瑞,辛春伟,等.1-(4-取代苯基)-4-苯基-5-(2-羟基苄基)氨基-1,2,3-三唑类衍生物的合成及抑菌活性[J].高等学校化学学报,2011,32(12):2806-2811.
[12]彭春勇,卢俊瑞,辛春伟,等.新型1,2,3-三唑类化合物的合成及抗菌构效关系[J].高等学校化学学报,2013,34(6):1394-1402.
[13]ADDLA D,JALLAPALLY A,GURRAM D,et al.Rational design,synthesis and antitubercular evaluation of novel 2-(trifluoromethyl)phenothiazine-[1,2,3]triazole hybrids[J].Bioorg Med Chem Lett,2014,24(1):233-236.
[14]HE YW,DONG CZ,ZHAO JY,et al.1,2,3-Triazole-containing derivatives of rupestonic acid:Click-chemical synthesis and antiviral activities against influenzaviruses[J].Eur J Med Chem,2014,76:245-255.
[15]王盟盟,段迎超,叶先炜,等.新型1,4-双哌嗪二硫代甲酸[1-取代(1,2,3-三唑)-4]-甲酯类化合物的设计、合成和抗肿瘤活性研究[J].有机化学,2013(11):2384-2390.
[16]DEMCHUK DV,SAMET AV,CHERNYSHEVA NB,et al.Synthesis and antiproliferative activity of conformationally restricted 1,2,3-triazole analogues of combretastatins in the sea urchin embryo model and against human cancer cell lines[J].Bioorg Med Chem,2014,22(2):738-755.
[17]TSUZUKI Y,TOMITA K,SHIBAMORI K,et al.Synthesis and structure-activity relationships of novel 7-substituted 1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acids as antitumor agents.Part 2[J].J Med Chem,2004,47(8):2097-2109.
[18]TOMITA K,TSUZUKI Y,SHIBAMORI K,et al.Synthesis and structure-activity relationships of novel 7-substituted 1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acids as antitumor agents.Part 1[J].J Med Chem,2002,45(25):5564-5575.
[19]BOTEVA AA,KRASNYKH OP.The methods of synthesis,modification,and biological activity of 4-quinolones[J].Chem Heterocycl com+,2009,45(7):757-785.
[20]LI XL,LIN YJ,YUAN YK,et al.Novel efficient anticancer agents and DNA-intercalators of 1,2,3-triazol-1,8-naphthalimides:design,synthesis,and biological activity[J].Tetrahedron,2011,67(12):2299-2304.