新型吲哚-嘧啶联芳类化合物的设计、合成及抗肿瘤活性研究
收稿日期: 2020-06-26
修回日期: 2020-08-04
网络出版日期: 2020-09-15
基金资助
国家自然科学基金(U1904163); 蛋白关键研究项目(2018YFE0195100); 食管癌防治国家重点实验室资助的开放基金(K2020000X)
Design, Synthesis and Anticancer Activity Studies of Novel Indole-Pyrimidine Biaryl Derivatives
Received date: 2020-06-26
Revised date: 2020-08-04
Online published: 2020-09-15
Supported by
the National Natural Science Foundation of China(U1904163); the Key Research Program of Proteins(2018YFE0195100); the Opening Fund from State Key Laboratory of Esophageal Cancer Prevention & Treatment(K2020000X)
设计合成了一系列新型的吲哚-嘧啶联芳类化合物, 并评估了它们对组蛋白去甲基化酶(LSD1)的抑制活性和5种肿瘤细胞系(MGC-803, PC-3, EC-109, PC-12和MCF-7)的抗增殖活性. 探讨了22个新型吲哚-嘧啶联芳类骨架衍生物的主要构效关系. 在这些化合物中, 1-(4-(4-(1-甲基-1 H-吲哚-3-基)嘧啶-2-基)哌嗪-1-基)-2-((3,4,5-三甲氧基苯基)氨基) 乙-1-酮(6i)展示出了潜在的LSD1抑制活性(IC 50=1.03 µmol/L), 而1-(4-(4-(1-甲基-1 H-吲哚-3-基)嘧啶-2-基)哌嗪-1-基)-2-(间甲苯胺)乙-1-酮(6c), 2-((4-丁基苯基）氨基)-1-(4-(4-(1-甲基-1 H-吲哚-3-基)嘧啶-2-基)哌嗪-1-基)乙-1-酮(6f)和2-((3-氟苯基)氨基)-1-(4-(4-(1-甲基-1 H-吲哚-3-基)嘧啶-2-基)哌嗪-1-基)乙-1-酮(6k)对PC-3细胞显示出潜在的抗肿瘤活性. 其中活性最强的化合物6k的对PC-3细胞系IC 50值为2.75 µmol/L, 可作为生物活性片段和开发更有效抗肿瘤药物的靶点化合物.
张丹青 , 柳旭 , 庞晓静 , 刘宏民 , 张秋荣 . 新型吲哚-嘧啶联芳类化合物的设计、合成及抗肿瘤活性研究[J]. 有机化学, 2021 , 41(1) : 267 -275 . DOI: 10.6023/cjo202006054
A series of novel indole-pyrimidine biaryl derivatives were designed, synthesized and evaluated for inhibitory activity against Lysine Specific Demethylase 1 (LSD1) and antiproliferative activity against five selected cancer cell lines (MGC-803, PC-3, EC-109, PC-12 and MCF-7). The priliminary structure-activity relationship (SAR) for this indole-pyrimidine biaryl scaffold was explored with evaluation of 22 variants of the structural class. Among these analogues, compound 1-(4-(4-(1-methyl-1 H-indol-3-yl)pyrimidin-2-yl)piperazin-1-yl)-2-((3,4,5-trimethoxyphenyl)amino)ethan-1-one (6i) exhibited the potential inhibitory activity against LSD1 (IC 50=1.03 µmol/L), compounds 1-(4-(4-(1-methyl-1 H-indol- 3-yl)pyrimidin-2-yl)piperazin-1-yl)-2-(m-tolylamino)ethan-1-one (6c), 2-((4-butylphenyl)amino)-1-(4-(4-(1-methyl-1 H-indol- 3-yl)pyrimidin-2-yl)piperazin-1-yl)ethan-1-one (6f) and 2-((3-fluorophenyl)amino)-1-(4-(4-(1-methyl-1 H-indol-3-yl)pyri- midin-2-yl)piperazin-1-yl)ethan-1-one (6k) showed the potential inhibitory activity aginst PC-3 cells. Especially, compound6k exhibited the best antitumor activity (IC 50=2.75 µmol/L), which was served as bioactive fragment and hit compound for developing more potent antitumor agents.
Key words： indole; pyrimidine; biaryl; antitumor
| [1] | Mullard A. Nat. Rev. Drug Discovery 2020, 19, 79. |
| [2] | Mullard A. Nat. Rev. Drug Discovery 2019, 18, 85. |
| [3] | Flick A.C.; Ding H.X.; Leverett C.A.; Fink S.J.; O'Donnell C.J. J. Med. Chem. 2018, 61, 7004. |
| [4] | Flick A.C.; Leverett C.A.; Ding H.X.; McInturff E.; Fink S.J.; Helal C.J.; O'Donnell C.J. J. Med. Chem. 2019, 62, 7340. |
| [5] | Yuan S.; Yu B.; Liu H.M. Adv. Synth. Catal. 2019, 361, 59. |
| [6] | Yuan S.; Chang J.; Yu B. Top. Curr. Chem. 2020, 378, 23. |
| [7] | Finlay M.R.; Anderton M.; Ashton S.; Ballard P.; Bethel P.A.; Box M.R.; Bradbury R.H.; Brown S.J.; Butterworth S.; Campbell A.; Chorley C.; Colclough N.; Cross D.A.; Currie G.S.; Grist M.; Hassall L.; Hill G.B.; James D.; James M.; Kemmitt P.; Klinowska T.; Lamont G.; Lamont S.G.; Martin N.; McFarland H.L.; Mellor M.J.; Orme J.P.; Perkins D.; Perkins P.; Richmond G.; Smith P.; Ward R.A.; Waring M.J.; Whittaker D.; Wells S.; Wrigley G.L. J. Med. Chem. 2014, 57, 8249. |
| [8] | Akue-Gedu R.; Debiton E.; Ferandin Y.; Meijer L.; Prudhomme M.; Anizon F.; Moreau P. Bioorg. Med. Chem. 2009, 17, 4420. |
| [9] | Kim S.H.; Sperry J. J. Nat. Prod. 2015, 78, 3080. |
| [10] | Ha H.H.; Kim J.S.; Kim B.M. Bioorg. Med. Chem. Lett. 2008, 18, 653. |
| [11] | Yadav R.R.; Sharma S.; Joshi P.; Wani A.; Vishwakarma R.A.; Kumar A.; Bharate S.B. Bioorg. Med. Chem. Lett. 2015, 25, 2948. |
| [12] | Huggins W.M.; Barker W.T.; Baker J.T.; Hahn N.A.; Melander R.J.; Melander C. ACS Med. Chem. Lett. 2018, 9, 702. |
| [13] | Xiong Y.; Wang E.; Huang Y.; Guo X.; Yu Y.; Du Q.; Ding X.; Sun Y. Stem Cell Rev. Rep. 2016, 12, 298. |
| [14] | Rivers A.; Vaitkus K.; Ruiz M.A.; Ibanez V.; Jagadeeswaran R.; Kouznetsova T.; DeSimone J.; Lavelle D. Exp. Hematol. 2015, 43, 546. |
| [15] | Naoki O.; Tomoyuki A.; Nakanobu H.; Masahiko S.; Jiro K.; Takashi U.; Shin S.; Masashi U.; Yutaka H.; Furukawa Y. Oncotarget 2018, 9, 6450. |
| [16] | Fu X.; Zhang P.; Yu B. Future Med. Chem. 2017, 9, 1227. |
| [17] | Yao D.; Zhou Y.; Zhu L.; Ouyang L.; Zhang J.; Jiang Y.; Zhao Y.; Sun D.; Yang S.; Yu Y.; Wang J. Eur. J. Med. Chem. 2017, 140, 155. |
| [18] | Keith J.M.; Apodaca R.; Tichenor M.; Xiao W.; Jones W.; Pierce J.; Seierstad M.; Palmer J.; Webb M.; Karbarz M.; Scott B.; Wilson S.; Luo L.; Wennerholm M.; Chang L.; Brown S.; Rizzolio M.; Rynberg R.; Chaplan S.; Breitenbucher J.G. ACS Med. Chem. Lett. 2012, 3, 823. |
| [19] | Reuberson J.; Horsley H.; Franklin R.J.; Ford D.; Neuss J.; Brookings D.; Huang Q.; Vanderhoydonck B.; Gao L.J.; Jang M.Y.; Herdewijn P.; Ghawalkar A.; Fallah-Arani F.; Khan A.R.; Henshall J.; Jairaj M.; Malcolm S.; Ward E.; Shuttleworth L.; Lin Y.; Li S.; Louat T.; Waer M.; Herman J.; Payne A.; Ceska T.; Doyle C.; Pitt W.; Calmiano M.; Augustin M.; Steinbacher S.; Lammens A.; Allen R. J. Med. Chem. 2018, 61, 6705. |
| [20] | Swanson D.M.; Dubin A.E.; Shah C.; Nasser N.; Chang L.; Dax,S.L.; Jetter, M.; Breitenbucher, J.G.; Liu, C.L.; Mazur, C; Lord, B.; Gonzales, L.; Hoey, K.; Rizzolio, M.; Bogenstaetter, M.; Codd, E.E.; Lee, D.H.; Zhang, S.P.; Chaplan, S.R. J. Med. Chem. 2005, 45, 1857. |
| [21] | Sanchez-Cespedes J.; Martinez-Aguado P.; Vega-Holm M.; Serna-Gallego A.; Candela J.I.; Marrugal-Lorenzo J.A.; Pachon J.; Iglesias-Guerra F.; Vega-Perez J.M. J. Med. Chem. 2016, 59, 5432. |
| [22] | Al-Ansary G.H.; Ismail M.A.; Abou El Ella D.A.; Eid S.; Abouzid K.A. Eur. J. Med. Chem. 2013, 68, 19. |
| [23] | Jian S.; Gao Q.L.; Wu B.W.; Li D.; Shi L.; Zhu T.; Lou J.F.; Jin C.Y.; Zhang Y.B.; Zhang S.Y.; Liu H.M. Eur. J. Med. Chem. 2019, 183, 111731. |
| [24] | Li N.; Xin J.; Ma Q.; Li E.; Meng Y.; Bao C.; Yang P.; Song P.; Cui F.; Cheng P.; Gu Y.; Zhao P.; Ke Y.; Liu H.; Zhang Q. Chin. J. Org. Chem. 2018, 38, 665. (in Chinese) |
| [24] | ( 栗娜, 辛景超, 马启胜, 李二冬, 孟娅琪, 包崇男, 杨鹏, 宋攀攀, 崔飞, 陈鹏举, 顾一飞, 赵培荣, 可钰, 刘宏民, 张秋荣, 有机化学, 2018, 38, 665.). |
| [25] | Xin J.; Li N.; Ma Q.; Li E.; Meng X.; Ke Y.; Liu H.; Zhang Q. Chin. J. Org. Chem. 2018, 38,451. (in Chinese) |
| [25] | ( 辛景超, 栗娜, 马启胜, 李二冬, 孟祥川, 可钰, 刘宏民, 张秋荣, 有机化学, 2018, 38, 451.). |
| [26] | Finlay M.R.; Anderton M.; Ashton S.; Ballard P.; Bethel P.A.; Box M.R.; Bradbury R.H.; Brown S.J.; Butterworth S.; Campbell A.; Chorley C.; Colclough N.; Cross D.A.; Currie G.S.; Grist M.; Hassall L.; Hill G.B.; James D.; James M.; Kemmitt P.; Klinowska T.; Lamont G.; Lamont S.G.; Martin N.; McFarland H.L.; Mellor M.J.; Orme J.P.; Perkins D.; Perkins P.; Richmond G.; Smith P.; Ward R.A.; Waring M.J.; Whittaker D.; Wells S.; Wrigley G.L. J. Med. Chem. 2014, 57, 8249. |
| [27] | Murthy Bandaru, S.S.; Bhilare, S.; Chrysochos, N.; Gayakhe, V.; Trentin, I.; Schulzke, C.; Kapdi, A.R. Org. Lett. 2018, 20, 473. |
| [28] | Zhan W.; Li D.; Che J.; Zhang L.; Yang B.; Hu Y.; Liu T.; Dong X. Eur. J. Med. Chem. 2014, 75, 11. |
/
| 〈 |
|
〉 |
