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.

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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

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