Synthesis and Evaluation in vitro of Novel Harmine Derivatives as Anticancer Activity Agents

doi:10.6023/cjoc202112015

Chinese Journal of Organic Chemistry ›› 2022, Vol. 42 ›› Issue (6): 1863-1871.DOI: 10.6023/cjoc202112015 Previous Articles Next Articles

NOTES

新型哈尔碱衍生物的合成与体外抗肿瘤活性研究

胡冬燕^a^,^b, 韩广田^b, 李喜安^b, 任华忠^b, 岳李荣^b, 郭力^a^,^*(), 封家福^b^,^*()

a 成都中医药大学药学院中药资源系统研究与开发利用国家重点实验室成都 611137
b 乐山职业技术学院四川乐山 614000

收稿日期:2021-12-07 修回日期:2022-02-12 发布日期:2022-02-25
通讯作者: 郭力, 封家福
基金资助:
四川省中医药管理局科技(2020JC0069); 乐山市科技计划(20SZD067); 乐山市科技计划(20NZD007); 乐山职业技术学院科研基金(KY2019015); 乐山职业技术学院科研基金(KY2019016)

Synthesis and Evaluation in vitro of Novel Harmine Derivatives as Anticancer Activity Agents

Dongyan Hu^a^,^b, Guangtian Han^b, Xi'an Li^b, Huazhong Ren^b, Lirong Yue^b, Li Guo^a(), Jiafu Feng^b()

a State Key Laboratory of Resources Systems Research and Development Utilization of Traditional Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137
b Leshan Vocational & Technical College, Leshan, Sichuan 614000

Received:2021-12-07 Revised:2022-02-12 Published:2022-02-25
Contact: Li Guo, Jiafu Feng
Supported by:
Sichuan Provincial Administration of Traditional Chinese Medicine Technology Plan(2020JC0069); Science and Technology Plan of Leshan(20SZD067); Science and Technology Plan of Leshan(20NZD007); Research Foundation of Leshan Vocational & Technical College(KY2019015); Research Foundation of Leshan Vocational & Technical College(KY2019016)

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Abstract

A series of novel 6-substituted harmine derivatives were synthesized from harmine in five steps: N⁹-methylation, bromination, Suzuki coupling, N-Boc deprotection, and amidation reaction. The structures of target compounds were confirmed by ¹H NMR, ¹³C NMR, and high-resolution mass spectra (HRMS). The in vitro antiproliferative activities were evaluated in a panel of cancer cell lines (HL-60, A549, SMMC-7721, MCF-7 and SW-480) via 3-(4,5-dimethylthiazol-2-yl)-5-(3- carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. The results indicated that some compounds had good to excellent activities, and especially the most potent compound was 3o, whose IC₅₀ values were 0.27 (against HL-60), 0.44 (against A549) and 0.048 μmol/L (against SMMC-7721), better than positive control drugs cisplatin and taxol (against SMMC-7721).

Key words: harmine, derivatization, antitumor activity

Cite this article

Dongyan Hu, Guangtian Han, Xi'an Li, Huazhong Ren, Lirong Yue, Li Guo, Jiafu Feng. Synthesis and Evaluation in vitro of Novel Harmine Derivatives as Anticancer Activity Agents[J]. Chinese Journal of Organic Chemistry, 2022, 42(6): 1863-1871.

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References 17

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Compd.	R¹	IC₅₀/(μmol•L^–1)^a
Compd.	R¹	HL-60	A549	SMMC-7721	MCF-7	SW-480
Harmine	—	44.71	36.47	17.43	27.75	22.08
3a	Phenyl	5.56	13.58	6.54	8.73	9.02
3b	p-Trifluoromethylphenyl	9.72	10.11	6.60	10.39	10.34
3c	p-Acetylphenyl	7.60	8.15	6.49	7.41	7.85
3d	Pyridine-4-yl	27.89	11.66	8.13	18.48	9.51
3e	Pyridine-3-yl	33.00	8.58	6.71	36.71	8.70
3f	Pyrimidine-5-yl	21.87	7.96	6.44	12.42	5.22
3g	Furan-3-yl	6.55	2.68	6.98	0.35	3.23
3h	Furan-2-yl	25.68	8.33	3.22	7.29	5.70
3i	Thiophene-2-yl	22.14	8.46	4.12	7.00	8.00
3j	Thiophene-3-yl	24.16	10.37	5.89	11.31	9.66
3k	2-Acetyl-thiophene-5-yl	7.70	1.63	20.71	29.92	9.48
3l	1-Methyl-1H-pyrazole-4-yl	9.86	3.85	0.35	0.94	2.00
3m	1-Methyl-1H-pyrazole-5-yl	79.99	60.81	33.20	58.97	60.66
3n	1-Methyl-1H-pyrazole-3-yl	5.96	25.42	23.19	14.34^c	15.47
3o	Isoquinolin-4-yl	0.27	0.44	0.048	22.34	2.01
3p	Isoquinolin-8-yl	NT^d	NT	2.52	NT	NT
3q	Isoquinolin-5-yl	NT	NT	2.76	NT	NT
3r	Quinolin-8-yl	NT	NT	3.23	NT	NT
3s	Quinolin-5-yl	NT	NT	0.17	NT	NT
3t	Naphthalen-1-yl	NT	NT	0.75	NT	NT
4	p-Aminophenyl	>100	8.62	6.66	22.68	9.08
顺铂^b	—	2.18	9.81	5.34	24.45	12.65
紫杉醇^b	—	<0.008	<0.008	0.16	<0.008	<0.008

Compd.	R¹	IC₅₀/(μmol•L^–1)^a
Compd.	R¹	HL-60	A549	SMMC-7721	MCF-7	SW-480
Harmine	—	44.71	36.47	17.43	27.75	22.08
3a	Phenyl	5.56	13.58	6.54	8.73	9.02
3b	p-Trifluoromethylphenyl	9.72	10.11	6.60	10.39	10.34
3c	p-Acetylphenyl	7.60	8.15	6.49	7.41	7.85
3d	Pyridine-4-yl	27.89	11.66	8.13	18.48	9.51
3e	Pyridine-3-yl	33.00	8.58	6.71	36.71	8.70
3f	Pyrimidine-5-yl	21.87	7.96	6.44	12.42	5.22
3g	Furan-3-yl	6.55	2.68	6.98	0.35	3.23
3h	Furan-2-yl	25.68	8.33	3.22	7.29	5.70
3i	Thiophene-2-yl	22.14	8.46	4.12	7.00	8.00
3j	Thiophene-3-yl	24.16	10.37	5.89	11.31	9.66
3k	2-Acetyl-thiophene-5-yl	7.70	1.63	20.71	29.92	9.48
3l	1-Methyl-1H-pyrazole-4-yl	9.86	3.85	0.35	0.94	2.00
3m	1-Methyl-1H-pyrazole-5-yl	79.99	60.81	33.20	58.97	60.66
3n	1-Methyl-1H-pyrazole-3-yl	5.96	25.42	23.19	14.34^c	15.47
3o	Isoquinolin-4-yl	0.27	0.44	0.048	22.34	2.01
3p	Isoquinolin-8-yl	NT^d	NT	2.52	NT	NT
3q	Isoquinolin-5-yl	NT	NT	2.76	NT	NT
3r	Quinolin-8-yl	NT	NT	3.23	NT	NT
3s	Quinolin-5-yl	NT	NT	0.17	NT	NT
3t	Naphthalen-1-yl	NT	NT	0.75	NT	NT
4	p-Aminophenyl	>100	8.62	6.66	22.68	9.08
顺铂^b	—	2.18	9.81	5.34	24.45	12.65
紫杉醇^b	—	<0.008	<0.008	0.16	<0.008	<0.008

Compd.	R²	IC₅₀/(μmol•L^–1)^a
Compd.	R²	HL-60	A549	SMMC-7721	MCF-7	SW-480
Harmine	—	44.71	36.47	17.43	27.75	22.08
5a	Methyl	>100	74.49	28.11	>100	17.08
5b	Ethyl	35.33	12.09	12.97	22.84	10.07
5c	Propyl	37.38	42.36	33.20	>100	>100
5d	Cyclohexyl	6.89	2.45	1.65	7.31	3.86
5e	Tetrahydropyran-4-yl	>100	>100	>100	>100	>100
5f	Pyridine-3-yl	8.63	6.57	>100	9.90	65.76
5g	Thiophene-3-yl	1.60	1.60	3.31	9.66	1.95
5h	Tthiazole-4-yl	1.53	10.27	3.06	>100	>100
5i	1-Methyl-1H-imidazole-4-yl	1.61	2.10	1.67	>100	5.08
5j	3-(Difluoromethyl)-1-methyl-1H-pyrazole-4-yl	0.37	0.41	1.53	1.92	1.35
顺铂^b	—	2.18	9.81	5.34	24.45	12.65
紫杉醇^b	—	<0.008	<0.008	0.16	<0.008	<0.008

Compd.	R²	IC₅₀/(μmol•L^–1)^a
Compd.	R²	HL-60	A549	SMMC-7721	MCF-7	SW-480
Harmine	—	44.71	36.47	17.43	27.75	22.08
5a	Methyl	>100	74.49	28.11	>100	17.08
5b	Ethyl	35.33	12.09	12.97	22.84	10.07
5c	Propyl	37.38	42.36	33.20	>100	>100
5d	Cyclohexyl	6.89	2.45	1.65	7.31	3.86
5e	Tetrahydropyran-4-yl	>100	>100	>100	>100	>100
5f	Pyridine-3-yl	8.63	6.57	>100	9.90	65.76
5g	Thiophene-3-yl	1.60	1.60	3.31	9.66	1.95
5h	Tthiazole-4-yl	1.53	10.27	3.06	>100	>100
5i	1-Methyl-1H-imidazole-4-yl	1.61	2.10	1.67	>100	5.08
5j	3-(Difluoromethyl)-1-methyl-1H-pyrazole-4-yl	0.37	0.41	1.53	1.92	1.35
顺铂^b	—	2.18	9.81	5.34	24.45	12.65
紫杉醇^b	—	<0.008	<0.008	0.16	<0.008	<0.008

新型哈尔碱衍生物的合成与体外抗肿瘤活性研究

Synthesis and Evaluation in vitro of Novel Harmine Derivatives as Anticancer Activity Agents

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