Synthesis, Crystal Structure and Antitumor Activity of Novel 5-Chloro-β-carboline Derivatives

doi:10.6023/cjoc202006026

Chinese Journal of Organic Chemistry ›› 2021, Vol. 41 ›› Issue (1): 400-406.DOI: 10.6023/cjoc202006026 Previous Articles Next Articles

NOTES

5-氯-β-咔啉衍生物的合成、晶体结构与抗肿瘤活性

孙跃^a, 郭亮^a, 范文玺^b, 陈伟^b, 张洁^a^,^*(), 代斌^a^,^*()

a 石河子大学化学化工学院新疆兵团化工绿色过程重点实验室新疆石河子 832003
b 新疆华世丹药物研究有限责任公司乌鲁木齐 830011

收稿日期:2020-06-15 修回日期:2020-08-06 发布日期:2020-08-27
通讯作者: 张洁, 代斌
作者简介:
* Corresponding authors. E-mail: zhangjie-xj@163.com; db_tea@shzu.edu.cn
基金资助:
石河子大学科研计划(SHYL-YB201804); 教育部长江学者和创新团队发展计划(IRT15R46); 石河子大学长江学者研究(CJXZ201601)

Synthesis, Crystal Structure and Antitumor Activity of Novel 5-Chloro-β-carboline Derivatives

Yue Sun^a, Liang Guo^a, Wenxi Fan^b, Wei Chen^b, Jie Zhang^a^,^*(), Bin Dai^a^,^*()

a Key Laboratory for Green Processing of Chemical Engineering of Xinjiang Bingtuan, School of Chemistry and Chemical Engineering, Shihezi University, Shihezi, Xinjiang 832003
b Xinjiang Huashidan Pharmaceutical Research Co., Ltd., Urumqi 830011

Received:2020-06-15 Revised:2020-08-06 Published:2020-08-27
Contact: Jie Zhang, Bin Dai
Supported by:
the Scientific Research Innovation Project in Shihezi University(SHYL-YB201804); the Program for Changjiang Scholars and Innovative Research Team in University(IRT15R46); the Yangtze River Scholar Research Project of Shihezi University(CJXZ201601)

1. cjoc202006026辅助材料.pdf(3050KB)

Abstract

Sixteen novel 5-chloro- β-carboline derivatives were synthesized from harmane in four steps: N ⁹-alkylation, nitration, reduction, and Borch reduction. The structures of target compounds were confirmed by ¹H NMR, ¹³C NMR, and HRMS. A single crystal of 5-chloro-1,9-dimethyl- N-(pyridin-3-ylmethyl)- β-carboline (5e) was cultured, and its single crystal structure was determined by X-ray diffraction study. The in vitro antiproliferative activities were evaluated in a panel of cancer cell lines (A549, BGC-823, CT-26, Bel-7402, and MCF-7) via methyl thiazolyl tetrazolium (MTT) assay. The results indicated that some compounds had good activities, and especially N-(2,6-difluorobenzyl)-1-methyl-5-chloro-9-(2,3,4,5,6-pentafluorobenzyl)- β- carboline-6-amine (5j) and N-(pyridin-3-ylmethyl)-1-methyl-5-chloro-9-(2,3,4,5,6-pentafluorobenzyl)- β-carboline-6-amine (5m) showed considerable antitumor activity with IC₅₀ values lower than 10 μmol•L ^–1 against four cancer cell lines.

Key words: 5-chloro-β-carboline, synthesis, antitumor, structure-activity relationship

Cite this article

Yue Sun, Liang Guo, Wenxi Fan, Wei Chen, Jie Zhang, Bin Dai. Synthesis, Crystal Structure and Antitumor Activity of Novel 5-Chloro-β-carboline Derivatives[J]. Chinese Journal of Organic Chemistry, 2021, 41(1): 400-406.

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References 32

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Compound	5e
Moiety formula	C ₁₉H ₁₇ClN ₄
M _r	336.82
Crystal system	monoclinic
Space group
Wavelength/nm	0.071073
a/nm	2.96276(15)
b/nm	1.15581(4)
c/nm	1.01513(5)
α/(°)	90
β/(°)	95.197(3)
γ/(°)	90
T/K	173.0
Volume (nm ³)	3.4619(3)
Z	8
M _u/mm ^–1	0.236
D _x/(g•cm ^–3)	1.362
F(000)	1488
h, k, l (max)	36, 14, 12
N _ref	3414
T _min, T _max	0.6059, 0.7455
θ(max)	23.19
(Δ/ σ) _max	0.019
(Δ ρ) _max	0.247 e/Å ³
wR ₂	0.1284
S	1.025
N _par	228

Compound	5e
Moiety formula	C ₁₉H ₁₇ClN ₄
M _r	336.82
Crystal system	monoclinic
Space group
Wavelength/nm	0.071073
a/nm	2.96276(15)
b/nm	1.15581(4)
c/nm	1.01513(5)
α/(°)	90
β/(°)	95.197(3)
γ/(°)	90
T/K	173.0
Volume (nm ³)	3.4619(3)
Z	8
M _u/mm ^–1	0.236
D _x/(g•cm ^–3)	1.362
F(000)	1488
h, k, l (max)	36, 14, 12
N _ref	3414
T _min, T _max	0.6059, 0.7455
θ(max)	23.19
(Δ/ σ) _max	0.019
(Δ ρ) _max	0.247 e/Å ³
wR ₂	0.1284
S	1.025
N _par	228

Compd.	R ⁶	R ⁹	IC ₅₀ ^a /(µmol•L ^–1)					log P ^b	tPSA ^c /nm ²
Compd.	R ⁶	R ⁹	A549	BGC-823	CT-26	Bel-7402	MCF-7	log P ^b	tPSA ^c /nm ²
5a	Ph	CH ₃	8.3±1.2	11.3±1.5	12.2±1.7	17.5±2.6	13.7±2.4	4.02	0.2763
5b	2,6-F ₂C ₆H ₃	CH ₃	12.0±2.3	8.4±0.7	9.5±1.1	20.7±2.5	8.4±0.3	4.33	0.2763
5c	o-F ₃CC ₆H ₄	CH ₃	15.4±1.4	16.7±0.7	20.5±2.3	15.9±0.8	7.1±0.7	4.94	0.2763
5d	3-(Methylthio)butyl	CH ₃	8.3±0.8	24.8±2.4	14.3±1.8	26.1±2.6	17.2±1.4	3.28	0.2763
5e	3-Pyridyl	CH ₃	14.2±0.6	8.3±0.7	9.4±0.5	16.2±1.8	6.5±0.4	2.68	0.3999
5f	p-ClC ₆H ₄	CH ₃	34.3±2.1	13.9±1.6	23.4±3.2	14.2±1.3	8.8±0.9	4.58	0.2763
5g	p-(CH ₃) ₂CHC ₆H ₄	CH ₃	25.3±1.9	13.8±0.8	14.7±0.8	25.8±2.4	17.9±1.1	5.25	0.2763
5h	p-CH ₃OC ₆H ₄	CH ₃	14.6±2.2	23.1±1.9	33.4±1.3	21.5±2.3	15.5±1.9	3.89	0.3686
5i	Ph	CH ₂C ₆F ₅	11.5±0.8	13.3±2.1	21.5±1.4	13.4±1.3	7.6±0.7	6.54	0.2763
5j	2,6-F ₂C ₆H ₃	CH ₂C ₆F ₅	7.2±0.6	7.1±0.4	12.4±1.1	5.7±0.4	8.3±0.4	6.86	0.2763
5k	o-F ₃CC ₆H ₄	CH ₂C ₆F ₅	12.4±0.5	6.4±0.7	15.3±1.6	24.9±3.2	8.6±0.8	7.46	0.2763
5l	3-(Methylthio)butyl	CH ₂C ₆F ₅	11.5±1.3	14.6±0.8	21.6±2.5	13.2±0.9	9.6±1.2	5.8	0.2763
5m	3-Pyridyl	CH ₂C ₆F ₅	8.7±0.6	10.5±1.4	7.3±0.7	6.4±1.1	6.7±0.7	5.2	0.3999
5n	p-ClC ₆H ₄	CH ₂C ₆F ₅	13.4±0.5	21.7±1.5	11.9±0.6	13.7±1.3	7.8±0.9	7.1	0.2763
5o	p-(CH ₃) ₂CHC ₆H ₄	CH ₂C ₆F ₅	7.3±0.7	13.4±0.9	13.2±1.4	10.8±0.7	8.4±1.2	7.78	0.2763
5p	p-CH ₃OC ₆H ₄	CH ₂C ₆F ₅	11.6±1.1	15.4±1.7	11.5±1.6	14.4±2.6	8.2±0.7	6.41	0.3686
Cisplatin			15.8±2.4	8.4±0.7	4.2±0.7	15.4±1.9	10.5±2.3

Compd.	R ⁶	R ⁹	IC ₅₀ ^a /(µmol•L ^–1)					log P ^b	tPSA ^c /nm ²
Compd.	R ⁶	R ⁹	A549	BGC-823	CT-26	Bel-7402	MCF-7	log P ^b	tPSA ^c /nm ²
5a	Ph	CH ₃	8.3±1.2	11.3±1.5	12.2±1.7	17.5±2.6	13.7±2.4	4.02	0.2763
5b	2,6-F ₂C ₆H ₃	CH ₃	12.0±2.3	8.4±0.7	9.5±1.1	20.7±2.5	8.4±0.3	4.33	0.2763
5c	o-F ₃CC ₆H ₄	CH ₃	15.4±1.4	16.7±0.7	20.5±2.3	15.9±0.8	7.1±0.7	4.94	0.2763
5d	3-(Methylthio)butyl	CH ₃	8.3±0.8	24.8±2.4	14.3±1.8	26.1±2.6	17.2±1.4	3.28	0.2763
5e	3-Pyridyl	CH ₃	14.2±0.6	8.3±0.7	9.4±0.5	16.2±1.8	6.5±0.4	2.68	0.3999
5f	p-ClC ₆H ₄	CH ₃	34.3±2.1	13.9±1.6	23.4±3.2	14.2±1.3	8.8±0.9	4.58	0.2763
5g	p-(CH ₃) ₂CHC ₆H ₄	CH ₃	25.3±1.9	13.8±0.8	14.7±0.8	25.8±2.4	17.9±1.1	5.25	0.2763
5h	p-CH ₃OC ₆H ₄	CH ₃	14.6±2.2	23.1±1.9	33.4±1.3	21.5±2.3	15.5±1.9	3.89	0.3686
5i	Ph	CH ₂C ₆F ₅	11.5±0.8	13.3±2.1	21.5±1.4	13.4±1.3	7.6±0.7	6.54	0.2763
5j	2,6-F ₂C ₆H ₃	CH ₂C ₆F ₅	7.2±0.6	7.1±0.4	12.4±1.1	5.7±0.4	8.3±0.4	6.86	0.2763
5k	o-F ₃CC ₆H ₄	CH ₂C ₆F ₅	12.4±0.5	6.4±0.7	15.3±1.6	24.9±3.2	8.6±0.8	7.46	0.2763
5l	3-(Methylthio)butyl	CH ₂C ₆F ₅	11.5±1.3	14.6±0.8	21.6±2.5	13.2±0.9	9.6±1.2	5.8	0.2763
5m	3-Pyridyl	CH ₂C ₆F ₅	8.7±0.6	10.5±1.4	7.3±0.7	6.4±1.1	6.7±0.7	5.2	0.3999
5n	p-ClC ₆H ₄	CH ₂C ₆F ₅	13.4±0.5	21.7±1.5	11.9±0.6	13.7±1.3	7.8±0.9	7.1	0.2763
5o	p-(CH ₃) ₂CHC ₆H ₄	CH ₂C ₆F ₅	7.3±0.7	13.4±0.9	13.2±1.4	10.8±0.7	8.4±1.2	7.78	0.2763
5p	p-CH ₃OC ₆H ₄	CH ₂C ₆F ₅	11.6±1.1	15.4±1.7	11.5±1.6	14.4±2.6	8.2±0.7	6.41	0.3686
Cisplatin			15.8±2.4	8.4±0.7	4.2±0.7	15.4±1.9	10.5±2.3

5-氯-β-咔啉衍生物的合成、晶体结构与抗肿瘤活性

Synthesis, Crystal Structure and Antitumor Activity of Novel 5-Chloro-β-carboline Derivatives

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