吲唑衍生物的合成及抗鼻咽癌活性评价
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摘要
目的合成两个吲唑衍生物,并初步评价其体外抗鼻咽癌活性。方法以6-溴-1H-吲唑为起始原料,通过Suzuki偶联和Buchwald-Hartwig偶联反应合成目标化合物(Z1和Z2);使用MTT法测定目标化合物对人鼻咽癌细胞株SUNE1和犬肾上皮细胞MDCK的增殖抑制作用。通过Annexin V-FITC/PI试剂盒检测Z2的凋亡诱导作用;利用细胞周期与细胞凋亡检测试剂盒检测Z2对细胞周期的影响。结果合成2个吲唑衍生物Z1和Z2;经~1H NMR、~(13)C NMR及MS(ESI-TOF)表征确认结构; Z1和Z2对SUNE1增殖抑制作用的IC_(50)值分别是(26.11±0.82)μmol/L和(18.46±1.40)μmol/L,阳性对照药顺铂的IC_(50)值为(8.96±2.35)μmol/L; Z1和Z2对MDCK增殖抑制作用弱(IC_(50)值均> 200μmol/L),顺铂的IC_(50)值为(8.45±0.68)μmol/L。Z2对SUNE1无凋亡诱导作用,可将SUNE1的细胞周期阻滞在G_1期。结论合成的吲唑衍生物具有抗增殖活性,但弱于阳性对照药顺铂,肾毒性低于顺铂。Z2通过将SUNE1阻滞在G_1期发挥抗增殖活性。
Objective To synthesize two indazole derivatives and evaluate their anti-nasopharyngeal carcinoma activities. Methods Target compounds were synthesized by Suzuki couple reaction and Buchwald-Hartwig couple reaction by using 6-bromo-1 H-indazole as starting material. Anti-proliferation activities against human nasopharyngeal carcinoma cell line SUNE1 and MDCK cells were evaluated by MTT assay. The apoptosis-inducing effects of Z2 were determined by Annexin V-FITC/PI apoptosis detection kit. The effect of Z2 on cell cycle of SUNE1 was determined by Cell Cycle and Apoptosis Analysis Kit. Results Indazole derivatives Z1 and Z2 were synthesized and characterized by ~1H NMR,~(13)C NMR and MS( ESI-TOF). The IC_(50) s of Z1,Z2 and cisplatin against SUNE1 cells were( 26. 11 ± 0. 82) μmol/L,( 18.46±1.40) μmol/L and( 8. 96 ± 2. 35) μmol/L respectively. Z1 and Z2 had little anti-proliferation activities against MDCK cells( IC_(50)> 200 μmol/L). The IC_(50) of cisplatin against MDCK cells was( 8.45±0.68) μmol/L. Z2 had no apoptosis-inducing effects on SUNE1 cell and Z2 induced G_1 phase arrest in SUNE1 cells. Conclusion The synthesized indazole derivatives has slightly weaker anti-proliferation activities than cisplatin, but they display lower nephrotoxicity. Z2 exerts anti-proliferation activities by inducing G_1 phase arrest in SUNE1 cells.
Objective To synthesize two indazole derivatives and evaluate their anti-nasopharyngeal carcinoma activities. Methods Target compounds were synthesized by Suzuki couple reaction and Buchwald-Hartwig couple reaction by using 6-bromo-1 H-indazole as starting material. Anti-proliferation activities against human nasopharyngeal carcinoma cell line SUNE1 and MDCK cells were evaluated by MTT assay. The apoptosis-inducing effects of Z2 were determined by Annexin V-FITC/PI apoptosis detection kit. The effect of Z2 on cell cycle of SUNE1 was determined by Cell Cycle and Apoptosis Analysis Kit. Results Indazole derivatives Z1 and Z2 were synthesized and characterized by ~1H NMR,~(13)C NMR and MS( ESI-TOF). The IC_(50) s of Z1,Z2 and cisplatin against SUNE1 cells were( 26. 11 ± 0. 82) μmol/L,( 18.46±1.40) μmol/L and( 8. 96 ± 2. 35) μmol/L respectively. Z1 and Z2 had little anti-proliferation activities against MDCK cells( IC_(50)> 200 μmol/L). The IC_(50) of cisplatin against MDCK cells was( 8.45±0.68) μmol/L. Z2 had no apoptosis-inducing effects on SUNE1 cell and Z2 induced G_1 phase arrest in SUNE1 cells. Conclusion The synthesized indazole derivatives has slightly weaker anti-proliferation activities than cisplatin, but they display lower nephrotoxicity. Z2 exerts anti-proliferation activities by inducing G_1 phase arrest in SUNE1 cells.
引文
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[2]TANG L L,CHEN W Q,XUE W Q,et al.Global trends in incidence and mortality of nasopharyngeal carcinoma[J].Cancer Letters,2016,374(1):22-30.
[3]CHUA M L,WEE J T,HUI E P,et al.Nasopharyngeal carcinoma[J].Lancet,2016,387(10022):1012-1024.
[4]SCHMIDT A,BEUTLER A,SNOVYDOVYCH B.Recent advances in the chemistry of indazoles[J].Eur J Org Chem,2010,2008(24):4073-4095.
[5]DONG J,ZHANG Q,WANG Z,et al.Recent advances in the development of indazole-based anticancer agents[J].Chem Med Chem,2018,13(15):1-19.
[6]SUN Y,SHAN Y Y,LI C S,et al.Discovery of novel antiangiogenesis agents.Part 8:Diaryl thiourea bearing 1H-indazole-3-amine as multi-target RTKs inhibitors[J].Eur J Med Chem,2017,63(141):373-385.
[7]SHAKIL N A,SINGH M K,SATHIYENDIRAN M,et al.Microwave synthesis,characterization and bio-efficacy evaluation of novel chalcone based 6-carbethoxy-2-cyclohexen-1-one and 2H-indazol-3-ol derivatives[J].Eur J Med Chem,2013,59(21):120-131.
[8]HUGO C,ALEJANDRA G,MERCEDES G,et al.Pharmacological properties of indazole derivatives:recent developments[J].Mini-Rev Med Chem,2005,5(10):869-878.
[9]BENCE S,PTER K,GYRGY G F,et al.Discovery of isatin and 1H-indazol-3-ol derivatives as d-amino acid oxidase(DAAO)inhibitors[J].Bioorg Med Chem,2018,345(17):2415-2419.
[10]LIU J,PENG X,DAI Y,et al.Design,synthesis and biological evaluation of novel FGFR inhibitors bearing an indazole scaffold[J].Org Biomol Chem,2015,13(28):7643-7654.
[11]SAMPSON P B,LIU Y,FORREST B,et al.The discovery of polo-like kinase 4 inhibitors:identification of(1R,2S)-2-{3-[(E)-4-(((cis)-2,6Dimethylmorpholino)methyl)styryl]-1H-indazol-6-yl}-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one(CFI-400945)as a potent,orally active antitumor agent[J].J Med Chem,2014,58(1):147-169.
[12]TOMASSI S,LATEGAHN J,ENGEL J,et al.Indazole-based covalent inhibitors to target drug resistant epidermal growth factor receptor[J].J Med Chem,2017,60(6):2361-2372.
[13]MEDINA J R,BECKER C J,BLACKLEDGE C W,et al.Structure-based design of potent and selective 3-phosphoinositidedependent kinase-1(PDK1)inhibitors[J].J Med Chem,2011,54(6):1871-1895.
[14]NAJAFOV A,SOMMER E M,AXTEN J M,et al.Characterization of GSK2334470,a novel and highly specific inhibitor of PDK1[J].Biochem J,2011,433(2):357-369.
[15]YANG C,HUANG X,LIU H,et al.PDK1 inhibitor GSK2334470 exerts antitumor activity in multiple myeloma and forms a novel multitargeted combination with dual m TORC1/C2 inhibitor PP242[J].Oncotarget,2017,8(24):39185-39197.
[16]MAEGAWA S,CHINEN Y,SHIMURA Y,et al.Phosphoinositidedependent protein kinase-1 is a potential novel therapeutic target in mantle cell lymphoma[J].Exp Hemat,2017,59:72-81.
[17]THATIPALLY S,ACHARYULU P V R,DUBEY P K.Pyridinium p-toluenesulfonate:A mild and efficient catalyst for the regioselective tetrahydropyranylation of indazole derivatives under solvent-free conditions[J].Asian J Chem,2011,23(1):451-454.
[18]SHARMA S K,GOYAL N.Protective effect of Heliotropium eichwaldi against cisplatin-induced nephrotoxicity in mice[J].中西医结合学报,2012,10(5):555-560.
[19]XU B,YAN WQ,XU X,et al.Combination of amino acid/dipeptide with ligustrazine-betulinic acid as antitumor agents[J].Eur J Med Chem,2017,130:26-38.
[20]王鹏龙,徐昕,李国梁,等.新型川芎嗪衍生物的合成及其抗癌活性研究[J].西北药学杂志,2014,29(1):58-64.
[21]XU B,CHU F,ZHANG Y,et al.A series of new ligustrazinetriterpenes derivatives as anti-tmor agents:design,synthesis,and biological evaluation[J].Int J Mol Sci,2015,16(9):21035-21055.
[22]CHU F,XU X,LI G,et al.Amino acid derivatives of ligustrazineoleanolic acid as new cytotoxic agents[J].Molecules,2014,19(11):18215-18231.