目的 设计合成含有噻唑啉酮结构片段的4-芳氧基-6,7-二取代喹啉类化合物,并对其体外抗肿瘤活性进行研究。方法 以c-Met激酶抑制剂cabozantinib为先导物,结合课题组已有的构效关系,运用拼合原理及局部修饰的方法,通过亲核取代、硝化、还原及缩合等反应合成目标化合物。采用均相时间分辨荧光法和3-(4, 5-二甲基噻唑-2)-2, 5-二苯基四氮唑溴盐法对其c-Met激酶抑制活性和体外抗肿瘤活性进行了评价。采用实时动态活细胞成像法进一步评价了化合物对肿瘤细胞的杀伤作用。结果 合成得到了17个新化合物,其结构经1H-NMR、13C-NMR及HRMS确证。体外生物活性测试结果显示,所有化合物对c-Met激酶、人非小细胞肺癌A549、人肝癌细胞HepG2及人乳腺癌细胞MDA-MB-231均有一定的抑制活性,其中化合物m2对A549、HepG2及MDA-MB-231具有较显著的杀伤作用,IC50值分别为2.45、4.01和1.05 μmol·L-1。结论 该系列化合物具有较好的抗肿瘤活性,具有进一步研究的意义。
Abstract
OBJECTIVE To design and synthesize 4-phenoxy-6,7-disubstituted quinolines possessing thiazolinone scaffolds and investigate their in vitro antitumor activities. METHODS Taking the c-Met kinase inhibitor cabozantinib as lead compound and based on the obtained SARs, combination principles and local modification, target compounds were prepared by nucleophilic substitution, nitration, reduction and condensation, etc. The c-Met inhibition and in vitro antitumor activities were evaluated by HTRF and MTT methods, respectively. The cytotoxicity against cancer cells was evaluated by real-time dynamic living cell imaging. RESULTS Seventeen novel compounds were obtained, and their structures were confirmed by 1H-NMR, 13C-NMR and HRMS. In vitro bioassay indicated that all the compounds showed inhibitory activities against A549, HepG2 and MDA-MB-231 cell lines as well as c-Met kinase. Compound m2 exhibited potent cytotoxicity with IC50 values of 2.45, 4.01, and 1.05 μmol·L-1, respectively. CONCLUSION The series of compounds show preferable antitumor activities, which are worthy of further study.
关键词
抗肿瘤 /
间叶上皮细胞转变因子 /
噻唑啉酮
{{custom_keyword}} /
Key words
antitumor /
c-Met kinase /
thiazolinone
{{custom_keyword}} /
中图分类号：
R914
{{custom_clc.code}}
({{custom_clc.text}})
{{custom_sec.title}}
{{custom_sec.title}}
{{custom_sec.content}}
参考文献
[1] GHISO E, GIORDANO S. Targeting MET: why, where and how?[J]. Curr Opin Pharmacol,2013, 13(4):511-518.
[2] FURGE K A, ZHANG Y W, VANDE WOUDE F E. Met receptor tyrosine kinase: enhanced signaling through adapter proteins[J]. Oncogene, 2009, 19(49):5582-5589.
[3] PETERS S, ADJEI A A. MET: a promising anticancer therapeutic target[J]. Nat Rev Clin Oncol, 2012, 9(2):314-326.
[4] JUNG K H, PRAK B H, HONG S S. Progress in cancer therapy targeting c-Met signaling pathway[J]. Arch Pharm Res, 2012, 35(4):595-604.
[5] UNDERNER T L, HERBERTZ T, MIKYOCZKI S J. Discovery of small molecule c-Met inhibitors: evolution and profiles of clinical candidates[J]. Anti-Cancer Agents in Med Chem, 2010, 10 (1):7-27.
[6] LIU X, ZHENG C, SUN L, et al. Synthesis of new chalcone derivatives bearing 2,4-thiazolidinedione and benzoic acid moieties as potential anti-bacterial agents[J]. Eur J Med Chem, 2011, 46(8):3469-3473.
[7] GERONIKAKI A A, LAGUNIN A A, HADJIPAVLOU-LITINA D I, et al. Computer-aided discovery of anti-inflammatory thiazolidinones with dual cyclooxygenase/lipoxygenase inhibition[J]. J Med Chem, 2008, 51(6):1601-1609.
[8] HAVRYLYUK D, MOSULA L, ZIMENKOVSKY B, et al. Synthesis and anticancer activity evaluation of 4-thiazolidinones containing benzothiazole moiety[J]. Eur J Med Chem, 2010, 45(11):5012-5021.
[9] VERMA A, SARAF S K. 4-Thiazolidinone-a biologically active scaffold[J]. Eur J Med Chem, 2008, 43(5):897-905.
[10] APPALANAIDU K, KOTCHERLAKOTA R, DADMAL T L,et al.Synthesis and biological evaluation of novel 2-imino-4-thiazolidinone derivatives as potent anti-cancer agents[J]. Bioorg Med Chem Lett, 2016, 26(21):5361-5368.
[11] WANG S, ZHAO Y, ZHANG G, et al. Design, synthesis and biological evaluation of novel4-thiazolidinones containingindolin-2-one moiety as potential antitumor agent[J]. Eur J Med Chem, 2011, 46(8): 3509-3518.
[12] D'ANGELO N D, BELLON S F, BOOKER S K, et al. Design, synthesis, and biological evaluation of potent c-Met inhibitors[J]. J Med Chem,2008, 51 (18):5766-5779.
[13] QI B H, MI B, ZHAI X, et al. Discovery and optimization of novel 4-phenoxy-6,7-disubstitutedquinolines possessing semicarbazones as c-Met kinase inhibitors[J]. Bioorg Med Chem, 2013, 21(17):5246-5260.
[14] BELLON S F, KAPLAN-LEFKO P, YANG Y, et al. c-Met inhibitors with novel binding mode show activity against several hereditary papillary renal cell carcinoma-related mutations[J]. J Biol Chem, 2008, 283 (5):2675-2683.
[15] WALSH D A, FRANZYSHEN S K, YANNI J M. Synthesis and antiallergy activity of 4-(diarylhydroxymethyl)-1-[3-(aryloxy)propyl)piperidines and structurally related compounds[J]. J Med Chem, 1989, 32(1):105-118.
[16] FETSCHER C A.6-Nitroveratraldehyde[J]. Org Synth,1953,33:65-68.
[17] HERNÁNDEZ S, MORENO I, SANMARTIN R, et al. Toward safer processes for C-C biaryl bond construction: catalytic direct C-H arylation and tin-free radical coupling in the synthesis of pyrazolophenanthridines[J]. J Org Chem, 2010, 75(2):434-441.
[18] BANNEN L C, CHAN D S, CHEN J, et al. c-Met Modulators and methods of use, WO2005030140A2 [P], 20050407.
[19] THIRUMURUGAN R, SRIRAM D, SAXENA A, et al. 2,4-Dimethoxyphenyl-semicarbazones with anticonvulsant activity against three animal models of seizures: synthesis and pharmacological evaluation[J]. Bioorg Med Chem, 2006, 14(9):3106-3112.
[20] AZAM F, EL-GNIDI B A, ALKSKAS I A. Combating oxidative stress in epilepsy: design, synthesis, quantum chemical studies and anticonvulsant evaluation of 1-(substituted benzylidene/ethylidene)-4-(naphthalen-1-yl)semicarbazides[J]. Eur J Med Chem, 2010, 45(7):2817-2826.
[21] MALI J R, PRATAP U R, NETANKAR P D, et al. An efficient synthetic route for quinazolinyl 4-thiazolidinones[J]. Tetrahedron Lett, 2009, 50(35):5025-5027.
[22] QI B H, TAO H Y, WU D, et al. Synthesis and biological evaluation of 4-phenoxy-6,7-disubstituted quinolines possessing semicarbazone scaffolds as selective c-Met inhibitirs[J]. Arch Pharm Chem Life Sci, 2013, 346(8):596-609.
[23] JIA J J, GUO Z Y, LIANG Y H, et al. Synthesis and anti-tumor activities of quercetin and its derivates[J]. Chin Pharm J(中国药学杂志), 2016, 51(23):2013-2017.
[24] FRASER C, DAWSON J C, DOWLING R, et al. Rapid discovery and structure activity relationships of pyrazolopyrimidines that potently suppress breast cancer cell growth via SRC kinase inhibition with exceptional selectivity over ABL kinase [J].J Med Chem, 2016, 59(10):4679-4710.
{{custom_fnGroup.title_cn}}
脚注
{{custom_fn.content}}
基金
国家自然科学基金项目资助(21562053);贵州省科学技术基金资助(黔科合J字[2014]2181号);贵州省科技合作计划资助(黔科合LH字[2015]7523号)
{{custom_fund}}
PDF(2490 KB)
