组蛋白去乙酰化酶抑制剂N-(6-氧代-6-(苯氨基)己基)-2-氨基苯甲酰胺类衍生物的设计、合成与活性评价
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摘要
目的:设计并合成新型的苯甲酰胺类组蛋白去乙酰化酶抑制剂,并对这些化合物进行生物活性评价筛选与计算机模拟研究。方法:以邻硝基苯甲酸、6-氨基己酸和取代苯胺为原料,合成10个具有同一新型锌离子螯合基团的目标化合物,并以MTT法评价化合物对细胞A549,HepG2,HeLa-570,WI-38的抑制活性,对筛选出活性好的化合物进行细胞周期与细胞凋亡实验,以检测化合物的周期阻滞作用与诱导凋亡能力,进行分子对接与动力学模拟实验,进一步展示化合物与配体的对接构象。结果:e3对Hep-G2的活性与阳性对照物SAHA相当(1. 9μmol·L~(-1)),且e3对正常细胞的毒性更低; e3对Hep-G2细胞G0/G1期具有较强的阻滞和一定程度的诱导细胞凋亡的双重作用; e3与HDAC的对接构象与SAHA的构象高度一致。结论:本研究设计的新型苯甲酰胺类组蛋白去乙酰化酶抑制剂具有较好的抑制肿瘤细胞增殖活性,对正常细胞具有较低的毒性,是一类新型锌离子螯合基团的HDAC抑制剂,值得进一步研究。
Objective: To design and synthesize a new type of benzamide histone deacetylase inhibitors and evaluate their vitro activity and computer simulation studies. Methods: Ten target compounds with the novel Zn2 +chelating groups were synthesized by o-nitrobenzoic acid,6-aminohexanoic acid and substituted aniline. The inhibitory effects on cell proliferation of target compounds were investigated by the MTT assay,and the A549,HepG2,HeLa-570 and WI-38 were chosen for the MTT experiment. The cell cycle and cell apoptosis experiments were performed on selected compounds with good vitro activity in order to detect the cycle arrest and induction of apoptosis of the compounds. Molecular docking and kinetic simulation experiments on selected compounds further demonstrate the docking conformations of compounds and ligands. Results: The activity of e3 on Hep-G2 was comparable to the positive control SAHA( 1. 9 μmol·L~(-1)),and e3 was less toxic to normal cells. What's more,e3 had a strong inhibitory effect on Hep-G2 cells in G0/G1 phase and a certain degree of induction of apoptosis. The docking conformation of e3 and HDAC was consistent with SAHA. Conclusions: 2-Amino-N-( 6-oxo-6-( phenylamino) hexyl)benzamides as HDACIs in our study proves effective in suppressing the proliferation of tumor cells,and has lesstoxic to normal cells. It is a new kind of HDAC inhibitor of zinc ion chelating group,which deserves further research.
Objective: To design and synthesize a new type of benzamide histone deacetylase inhibitors and evaluate their vitro activity and computer simulation studies. Methods: Ten target compounds with the novel Zn2 +chelating groups were synthesized by o-nitrobenzoic acid,6-aminohexanoic acid and substituted aniline. The inhibitory effects on cell proliferation of target compounds were investigated by the MTT assay,and the A549,HepG2,HeLa-570 and WI-38 were chosen for the MTT experiment. The cell cycle and cell apoptosis experiments were performed on selected compounds with good vitro activity in order to detect the cycle arrest and induction of apoptosis of the compounds. Molecular docking and kinetic simulation experiments on selected compounds further demonstrate the docking conformations of compounds and ligands. Results: The activity of e3 on Hep-G2 was comparable to the positive control SAHA( 1. 9 μmol·L~(-1)),and e3 was less toxic to normal cells. What's more,e3 had a strong inhibitory effect on Hep-G2 cells in G0/G1 phase and a certain degree of induction of apoptosis. The docking conformation of e3 and HDAC was consistent with SAHA. Conclusions: 2-Amino-N-( 6-oxo-6-( phenylamino) hexyl)benzamides as HDACIs in our study proves effective in suppressing the proliferation of tumor cells,and has lesstoxic to normal cells. It is a new kind of HDAC inhibitor of zinc ion chelating group,which deserves further research.
引文
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[2]李秀艳,陶娌娜,张杰,等.脾多肽注射液辅助化疗治疗肿瘤的疗效与安全性meta分析[J].中国现代应用药学,2019,36(8):977-984.
[3]车文军,李志裕,尤启冬.抗肿瘤药物新靶点与新药研究[J].药学进展,2007,31(6):247-253.
[4]MANN BS,JOHNSON JR,COHEN MH,et al.FDA approval summary:vorinostat for treatment of advanced primary cutaneous T-cell lymphoma[J].Oncologist,2007,12(10):1247-1252.
[5]BAILEY H,STENEHJEM DD,SHARMA S.Panobinostat for the treatment of multiple myeloma:the evidence to date[J].JBlood Med,2015,6:269-276.
[6]SHARMA S,AHMAD M,BHAT JA,et al.Design,synthesis and biological evaluation of b-boswellic acid based HDAC inhibitors as inducers of cancer cell death[J].Bioorg Med Chem Lett,2014,24(19):4729-4734.
[7]BANERJI B,CHATTERJEE M,PAL U,et al.Molecular details of acetate binding to a new diamine receptor by NMR and FT-IRanalyses[J].J Phys Chem A,2016,120(15):2330-2341.
[8]李上标,裴淑艳,蒋超,等.MTT比色法研究应用进展[J].西北民族大学学报(自然科学版),2013,34(91):68-91.
[9]贺殿,马尚贤,郭青欣,等.苯取代异羟肟酸类组蛋白去乙酰化酶抑制剂的合成及体外抗肿瘤活性评价[J].中国新药杂志,2014,23(12):1438-1446.
[10]贾忠,张阳,李靖,等.新型苯乙酰胺类组蛋白去乙酰化酶抑制剂的合成及活性评价[J].中国新药杂志,2015,24(15):106-111.
[11]FENG TT,WANG H,SU H,et al.Novel N-hydroxyfurylacrylamide-based histone deacetylase(HDAC)inhibitors with branched CAP group(Part 2)[J].Bioorgan Med Chem,2013,21(17):5339-5354.
[12]BERENDSEN HJC,POSTMA JPM,GUNSTEREN WFV,et al.Molecular dynamics with coupling to an external bath[J].JChem Phys,1984,81(8):3684-3690.
[13]DUAN Y,WU C,CHOWDHURY S,et al.A point-charge force field for molecular mechanics simulations of proteins based on condensed-phase quantum mechanical calculations[J].J Comput Chem,2003,24(16):1999-2012.
[14]ESSMANN U,PERERA L,BERKOWITZ ML,et al.A smooth particle mesh Ewald method[J].J Chem Phys,1995,103(19):8577-8593.
[15]JAKALIAN A,JACK DB,BAYLY CI.Fast,efficient generation of high-quality atomic charges.AM1-BCC model:II.Parameterization and validation[J].J Comput Chem,2002,23(16):1623-1641.