Design, Synthesis and Anticancer Activity Studies of Novel Indole-Pyrimidine Biaryl Derivatives

doi:10.6023/cjo202006054

Chinese Journal of Organic Chemistry ›› 2021, Vol. 41 ›› Issue (1): 267-275.DOI: 10.6023/cjo202006054 Previous Articles Next Articles

Article

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

张丹青^a^,^b, 柳旭^a^,^b, 庞晓静^a^,^b, 刘宏民^a^,^b^,^c^,^*(), 张秋荣^a^,^b^,^c^,^*()

a 郑州大学药学院郑州 450001
b 新药创制与药物安全性评价河南省协同创新中心郑州 450001
c 教育部药物制备关键技术重点实验室郑州 450001

收稿日期:2020-06-26 修回日期:2020-08-04 发布日期:2020-09-15
通讯作者: 刘宏民, 张秋荣
作者简介:
* Corresponding authors. E-mail: liuhm@zzu.edu.cn; zqr409@yeah.net
† 作者对文章贡献一致(The authors contributed equally to this work).
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

Danqing Zhang^a^,^b, Xu Liu^a^,^b, Xiaojing Pang^a^,^b, Hongmin Liu^a^,^b^,^c^,^*(), Qiurong Zhang^a^,^b^,^c^,^*()

a School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001
b Co-Innovation Center of Henan Province for New Drug and Preclinical Safety, Zhengzhou 450001
3 Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou 450001

Received:2020-06-26 Revised:2020-08-04 Published:2020-09-15
Contact: Hongmin Liu, Qiurong Zhang
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)

1. 210267S.pdf(2262KB)

Abstract

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

Cite this article

Danqing Zhang, Xu Liu, Xiaojing Pang, Hongmin Liu, Qiurong Zhang. Design, Synthesis and Anticancer Activity Studies of Novel Indole-Pyrimidine Biaryl Derivatives[J]. Chinese Journal of Organic Chemistry, 2021, 41(1): 267-275.

Export EndNote|Reference Manager|ProCite|BibTeX|RefWorks

share this article

Fig. & Tab. 6

References 28

[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)
	( 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)
	( 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.

Compd.	R	Inhibitory rate ^a /%	Compd.	R	Inhibitory rate ^a /%
6a	—	<10	6m	2-Cl	<10
6b	2-Me	<10	6n	3-Cl	<10
6c	3-Me	<10	6o	4-Cl	<10
6d	4-Me	30	6p	2-Br	<10
6e	4-Et	<10	6q	3-Br	<10
6f	4- ⁿ Bu	11	6r	4-Br	32
6g	2-OMe	<10	6s	3-Cl-4-F	41
6h	3-OMe	11	6t	3-Br-4-F	<10
6i	3,4,5-(OMe) ₃	55 (1.03 µmol/L)	6u	2,4-Cl ₂	<10
6j	2-F	<10	6v	4-CN	12
6k	3-F	<10	ORY-1001 ^b		99
6l	4-F	20

Compd.	R	Inhibitory rate ^a /%	Compd.	R	Inhibitory rate ^a /%
6a	—	<10	6m	2-Cl	<10
6b	2-Me	<10	6n	3-Cl	<10
6c	3-Me	<10	6o	4-Cl	<10
6d	4-Me	30	6p	2-Br	<10
6e	4-Et	<10	6q	3-Br	<10
6f	4- ⁿ Bu	11	6r	4-Br	32
6g	2-OMe	<10	6s	3-Cl-4-F	41
6h	3-OMe	11	6t	3-Br-4-F	<10
6i	3,4,5-(OMe) ₃	55 (1.03 µmol/L)	6u	2,4-Cl ₂	<10
6j	2-F	<10	6v	4-CN	12
6k	3-F	<10	ORY-1001 ^b		99
6l	4-F	20

Compd.	R	IC ₅₀ ^a /(µmol•L ^–1)
Compd.	R	MGC-803	PC-3	EC-109	PC-12	MCF-7
6a ^b	—	>40	6.80±0.53	>40	27.74±1.00	20.86±2.85
6b	2-Me	13.65±1.13	>40	>40	>40	>40
6c	3-Me	>40	4.10±0.46	>40	25.15±0.34	22.29±0.68
6d	4-Me	>40	29.16±3.15	>40	>40	>40
6e	4-Et	14.68±1.20	10.21±2.13	>40	31.29±1.41	8.19±0.09
6f	4- ⁿ Bu	>40	6.10±1.52	>40	>40	12.51±0.79
6g	2-OMe	4.35±1.33	>40	>40	>40	10.69±1.59
6h	3-OMe	>40	>40	>40	>40	>40
6i	3,4,5-(OMe) ₃	14.50±1.79	15.62±3.14	9.34±2.08	8.49±1.14	10.55±0.21
6j	2-F	23.53±1.03	18.45±2.11	>40	>40	>40
6k	3-F	>40	2.75±0.20	>40	27.74±0.74	24.67±0.46
6l	4-F	>40	13.23±1.32	>40	>40	>40
6m	2-Cl	20.41±0.86	>40	>40	>40	>40
6n	3-Cl	>40	11.56±2.01	>40	>40	>40
6o	4-Cl	>40	25.33±1.26	>40	>40	>40
6p	2-Br	17.12±1.38	26.81±1.32	>40	>40	>40
6q	3-Br	>40	10.20±1.31	>40	>40	>40
6r	4-Br	>40	>40	>40	>40	>40
6s	3-Cl-4-F	26.58±1.65	>40	13.43±1.82	16.47±0.17	30.33±2.36
6t	3-Br-4-F	>40	22.88±3.53	26.02±0.71	31.43±0.17	>40
6u	2,4-Cl ₂	>40	>40	>40	>40	>40
6v	4-CN	6.24±1.44	>40	19.95±1.92	6.51±0.11	>40
5-Fu		7.26±1.21	15.30±1.56	18.42±1.67	20.12±1.68	15.81±1.24

Compd.	R	IC ₅₀ ^a /(µmol•L ^–1)
Compd.	R	MGC-803	PC-3	EC-109	PC-12	MCF-7
6a ^b	—	>40	6.80±0.53	>40	27.74±1.00	20.86±2.85
6b	2-Me	13.65±1.13	>40	>40	>40	>40
6c	3-Me	>40	4.10±0.46	>40	25.15±0.34	22.29±0.68
6d	4-Me	>40	29.16±3.15	>40	>40	>40
6e	4-Et	14.68±1.20	10.21±2.13	>40	31.29±1.41	8.19±0.09
6f	4- ⁿ Bu	>40	6.10±1.52	>40	>40	12.51±0.79
6g	2-OMe	4.35±1.33	>40	>40	>40	10.69±1.59
6h	3-OMe	>40	>40	>40	>40	>40
6i	3,4,5-(OMe) ₃	14.50±1.79	15.62±3.14	9.34±2.08	8.49±1.14	10.55±0.21
6j	2-F	23.53±1.03	18.45±2.11	>40	>40	>40
6k	3-F	>40	2.75±0.20	>40	27.74±0.74	24.67±0.46
6l	4-F	>40	13.23±1.32	>40	>40	>40
6m	2-Cl	20.41±0.86	>40	>40	>40	>40
6n	3-Cl	>40	11.56±2.01	>40	>40	>40
6o	4-Cl	>40	25.33±1.26	>40	>40	>40
6p	2-Br	17.12±1.38	26.81±1.32	>40	>40	>40
6q	3-Br	>40	10.20±1.31	>40	>40	>40
6r	4-Br	>40	>40	>40	>40	>40
6s	3-Cl-4-F	26.58±1.65	>40	13.43±1.82	16.47±0.17	30.33±2.36
6t	3-Br-4-F	>40	22.88±3.53	26.02±0.71	31.43±0.17	>40
6u	2,4-Cl ₂	>40	>40	>40	>40	>40
6v	4-CN	6.24±1.44	>40	19.95±1.92	6.51±0.11	>40
5-Fu		7.26±1.21	15.30±1.56	18.42±1.67	20.12±1.68	15.81±1.24

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

Design, Synthesis and Anticancer Activity Studies of Novel Indole-Pyrimidine Biaryl Derivatives

RichHTML

PDF

Supporting Info.

Knowledge

Abstract

Cite this article

share this article

Fig. & Tab. 6

References 28

Related Articles 15

Recommended Articles 0

Metrics

Comments

[1]	Qinggang Mei, Qinghan Li. Recent Progress of Visible Light-Induced the Synthesis of C(3) (Hetero)arylthio Indole Compounds [J]. Chinese Journal of Organic Chemistry, 2024, 44(2): 398-408.
[2]	Penghui Li, Qingyang Xie, Fuxian Wan, Yuanhong Zhang, Lin Jiang. Synthesis and Fungicidal Activity of Novel Substituted Pyrimidine-5-carboxamides Bearing Cyclopropyl Moiety [J]. Chinese Journal of Organic Chemistry, 2024, 44(2): 650-656.
[3]	Bozhen Wang, Jie Zhang, Chunhui Nian, Mingming Jin, Miaomiao Kong, Wulan Li, Wenfei He, Jianzhang Wu. Synthesis and Antitumor Activity of 3,4-Dichlorophenyl Amides [J]. Chinese Journal of Organic Chemistry, 2024, 44(1): 232-241.
[4]	Chuantao Zhu, Song Wang, Yifan Zhao, Piet Herdewijn, Fengwu Liu. Synthesis of Novel 2,2'-Anhydro-L-threosylpyrimidine Phosphonates [J]. Chinese Journal of Organic Chemistry, 2023, 43(9): 3167-3173.
[5]	Dandan Sui, Nannan Cen, Ruoqu Gong, Yang Chen, Wenbo Chen. Supporting-Electrolyte-Free Electrochemical Synthesis of Trifluoromethylated Oxindoles in Continuous Flow [J]. Chinese Journal of Organic Chemistry, 2023, 43(9): 3239-3245.
[6]	Wenfeng Bei, Jian Pan, Dongmei Ran, Yilin Liu, Zhen Yang, Ruokun Feng. Cobalt-Catalyzed [4+2] Annulation of Indole Carboxamide with Diynes and Monoacetylene: Direct Access to γ-Carbolinones [J]. Chinese Journal of Organic Chemistry, 2023, 43(9): 3226-3238.
[7]	Yingke Feng, He Wang, Mengxing Cui, Ran Sun, Xin Wang, Yang Chen, Lei Li. Visible-Light-Induced Difluoroalkylated Cyclization of Novel Functionalized Aromatic Isocyanides [J]. Chinese Journal of Organic Chemistry, 2023, 43(8): 2913-2925.
[8]	Yi Wang, Jian Zhang, Yangzi Liu, Xiaoyan Luo, Weiping Deng. Palladium-Catalyzed Asymmetric [3＋4] Cycloadditions for the Construction of Cyclohepta[b]indoles [J]. Chinese Journal of Organic Chemistry, 2023, 43(8): 2864-2877.
[9]	Hai Lin, Huixiang Nie, Anlin Zhao, Tao Wang, Jin Luo. Synthesis and Herbicidal Activity of Novel Pyrimido[5,4-e]-[1,2,4]triazolo[1,5-c]pyrimidine Derivatives [J]. Chinese Journal of Organic Chemistry, 2023, 43(7): 2462-2475.
[10]	Lixing Sun, Tingting Sun, Haiqing Wang, Shufang Wu, Xiaoye Wang, Tianya Liu, Yuchen Zhang. Lewis Acid-Catalyzed [2+4] Cyclization of 3-Alkyl-2-vinylindoles with α,β-Unsaturated N-Sulfonyl Ketimines [J]. Chinese Journal of Organic Chemistry, 2023, 43(6): 2178-2188.
[11]	Zeren Sun, Bingxin Zhai, Guangchao He, Hui Shen, Linya Chen, Shan Zhang, Yi Zou, Qihua Zhu, Yungen Xu. Synthesis and Anti-inflammatory Evaluation of Novel 1,2,3-Triazole Derivatives [J]. Chinese Journal of Organic Chemistry, 2023, 43(6): 2143-2155.
[12]	Panxing Pang, Rong Ning, Chuang Zhu, Wenjie Huang, Xianli Ma, Caina Jiang, Fangyao Li, Xiaoqun Zhou. Synthesis and in Vitro Antitumor Activity of Matrine Semicarbazide Derivatives [J]. Chinese Journal of Organic Chemistry, 2023, 43(6): 2126-2135.
[13]	Mingyang Pang, Honghong Chang, Zhang Feng, Juan Zhang. Recent Advances in Transition-Metal-Catalyzed Tandem Dearomatization of Indoles [J]. Chinese Journal of Organic Chemistry, 2023, 43(4): 1271-1291.
[14]	Hua Huang, Xin Li, Jianke Su, Qiuling Song. Difluorocarbene-Enabled Synthesis of 3-Substituted-2-oxoindoles from o-Vinylanilines [J]. Chinese Journal of Organic Chemistry, 2023, 43(3): 1146-1156.
[15]	Jinxiao Zhao, Tonghui Wei, Sen Ke, Yi Li. Visible Light-Catalyzed Synthesis of Difluoroalkylated Polycyclic Indoles [J]. Chinese Journal of Organic Chemistry, 2023, 43(3): 1102-1114.