新型含有金刚烷苯乙烯结构单元化合物的合成和初步抗肿瘤增殖

doi:10.11944/j.issn.1000-0518.2018.04.170147

摘要/Abstract

摘要：

以金刚烷苯乙烯为结构单元,设计合成了3个含有亲水性基团的新型小分子(8a、8b和8c),利用核磁共振谱、红外光谱和高分辨质谱等技术手段对其进行了结构表征。用1-溴代金刚烷作为原料在Pd/C和K₂CO₃的作用下发生傅克烷基化反应高产率得到金刚烷甲苯(2),随后在N-溴代琥珀酰亚胺(NBS)和(三苯基膦烯基)乙酸甲酯过氧化苯甲酰(BPO)的作用下发生溴代反应得到了金刚烷苄基溴的化合物3,苄基溴在酸性条件下氧化生成醛(4),该醛与维蒂希试剂发生Wittig反应得到甲酸甲酯(5),随后发生碱性条件水解得到重要的中间体6。最后该中间体与3个结构不同的苯胺类化合物发生偶联反应生成了3个目标化合物。通过MTS法评价了3个化合物对人肝癌细胞(SMMC7721)、乳腺癌细胞(MCF-7)、宫颈癌细胞(Hela)、肺癌细胞(A549)的增殖抑制活性。结果表明,部分化合物表现出较好的抑制活性。其中,目标化合物8c对人肝癌细胞表现出较好的抗肿瘤活性(IC₅₀=1.6 μmol/L或0.73 mg/L),与现有药物阿霉素相当 (0.44 mg/L),有望成为潜在的抗肿瘤药物分子。该类化合物可能在靶向抗肿瘤药物研发方面具有较好的研究前景,所合成的金刚烷苯乙烯类衍生物的抗肿瘤活性、靶点及作用机制还有待进一步研究。

关键词: 金刚烷苯乙烯, 合成, 抗肿瘤活性, MTS

Abstract:

Three aniline p-adamantanylcinnamides(8a~8c) were designed and synthesized from cross coupling of 1-bromoadamantane with toluene followed by oxidation, homologation and amidation. The inhibitory assays of these compounds against human hepatocellular carcinoma cell SMMC7721, breast cancer cell MCF-7, cervical cancer cell Hela and lung cancer cell A549 by MTS method showed that compound 8c exhibited good antitumor activity against human hepatoma cells(IC₅₀=1.6 μmol/L or 0.73 mg/L) compared with doxorubicin(0.44 mg/L). This indicates that aniline p-adamantanylcinnamide is a good template for the development of anti-tumor drugs. The antitumor activity, cellular targets and the mode of action of aniline p-adamantanylcinnamide derivatives will be further studied.

Key words: adamantane styrene, synthesis, antitumor activity, MTS

桂舒雅,熊昊,林智,夏霖亚,钟启升,李东风,侯瑞斌,夏艳. 新型含有金刚烷苯乙烯结构单元化合物的合成和初步抗肿瘤增殖[J]. 应用化学, 2018, 35(4): 420-425.

GUI Shuya,XIONG Hao,LIN Zhi,XIA Linya,ZHONG Qisheng,LI Dongfeng,HOU Ruibin,XIA Yan. Synthesis and Primary Antitumor Proliferation of p-Adamantanylcinnamides[J]. Chinese Journal of Applied Chemistry, 2018, 35(4): 420-425.

参考文献

[1]	Magull-Seltenreich A,Zeller W J.Sensitization of Human Colon Tumour Cell Lines to Carmustine by Depletion of O6-alkylguanine-DNA Alkyl Transferase[J]. J Cancer Res Clin Oncol,1995,121(4):225-229.
[2]	Hensing T A.Clinical Evaluation and Staging of Patients Who Have Lung Cancer[J]. Hematol/Oncol Clin North Am,2005,19(2):219-235.
[3]	Schrama D,Reisfeld R A,Becker J C.Antibody Targeted Drugs as Cancer Therapeutics[J]. Nat Rev Drug Discovery,2006,5(2):147-159.
[4]	Conklin K A.Dietary Antioxidants During Cancer Chemotherapy:Impact On Chemotherapeutic Effectiveness and Development of Side Effects[J]. Nutr Cancer,2000,37(1):1-18.
[5]	Chabner B A,Roberts T G.Chemotherapy and the War on Cancer[J]. Nat Rev Cancer,2005,5(1):65-72.
[6]	LIU Hong,YANG Benming.The New Clinical Uses of Amantadine[J]. Tianjing Pharm,1996,8(3):32-33(in Chinese). 刘红,杨本明. 金刚烷胺的临床新用途[J]. 天津药学,1996,8(3):32-33.
[7]	GE Xiaozhong,YING Huanghui,CHEN Xiao,et al. The Research Progress of Adamantane Drugs[J]. Chinese J Pharm,2003,34(11):583-586(in Chinese). 葛孝忠,应黄惠,陈晓,等. 金刚烷类药物的研究进展[J]. 中国医药工业杂志,2003,34(11):583-586.
[8]	Baum K,Archibald T G.1,3-Diethynyladamantane and Methods of Polymerization Thereof:U.S.Patent 4,918,158[P]. 1990.
[9]	Lee K,Kang J E,Park S K,et al. LW6,a Novel HIF-1 Inhibitor, Promotes Proteasomal Degradation of HIF-1α via Upregulation of VHL in a Colon Cancer Cell Line[J]. Biochem Pharmacol,2010,80(7):982-989.
[10]	Boovanahalli S K,Jin X,Jin Y,et al. Synthesis of (Aryloxyacetylamino)-Isonicotinic/Nicotinic Acid Analogues as Potent Hypoxia-Inducible Factor(HIF)-1α Inhibitors[J]. Bioorg Med Chem Lett,2007,17(22):6305-6310.
[11]	Nakamura H,Yasui Y,Maruyama M,et al. Development of Hypoxia-Inducible Factor(HIF)-1α Inhibitors: Effect of Ortho-Carborane Substituents on HIF Transcriptional Activity Under Hypoxia[J]. Bioorg Med Chem Lett,2013,23(3):806-810.
[12]	Naik R,Won M,Kim B K,et al. Synthesis and Structure-Activity Relationship of (E)-Phenoxyacrylic Amide Derivatives as Hypoxia-Inducible Factor(HIF) 1α Inhibitors[J]. J Med Chem,2012,55(23):10564-10571.
[13]	Won M S,Im N,Park S,et al. A Novel Benzoimidazole Analogue Inhibits the Hypoxia-Inducible Factor(HIF)-1 Pathway[J]. Biochem Biophys Res Commun,2009,385(1):16-21.
[14]	XUE Yan,CHEN Jianzhong.Inhibitory Study of Adriamycin Against Liver Cancer Cell SMMC-7721[J]. Shaanxi Med J,2000,29(1):56-57(in Chines). 薛研,陈建宗. 阿霉素对人肝癌细胞SMMC-7721抑制作用的研究[J]. 陕西医学杂志,2000,29(1):56-57.

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