新型5位与6位取代的吲唑类衍生物的合成及抗肿瘤活性研究

doi:10.6023/cjoc202107049

摘要/Abstract

为了寻找高效低毒的新型抗肿瘤药物, 设计并合成了新型的5位与6位取代的吲唑类化合物. 采用噻唑蓝(MTT)法对目标化合物在PC-3(人前列腺癌细胞)、MCF-7(人乳腺癌细胞)、HepG-2(人肝癌细胞)和MGC-803(人胃癌细胞)四种人类癌细胞的抗增殖活性进行评价. 结果显示大部分化合物对PC-3具有特异性的抗增殖活性. 其中, N-(1-苄基- 1H-1,2,3-三唑-4-基)甲基)-1-异丙基-1H-吲哚唑-5-羧酰胺(8a)和N-[(1-苄基-1H-1,2,3-三唑-4-基)甲基]-1-异丙基-1H-吲唑- 6-甲酰胺(14a)对PC-3细胞的抗增殖活性较好, IC50值分别为6.21和6.43 μmol/L, 为前列腺癌抗肿瘤药物的研究提供了思路.

关键词: 吲唑, 癌症, 抗肿瘤活性, 前列腺癌

In order to search for new antitumor drugs with high efficiency and low toxicity, 5- and 6-substituted indazole compounds were designed and synthesized. The antiproliferative activity of target compounds in four human cancer cells, PC-3 (human prostate cancer cell), MCF-7 (human breast cancer cell), HepG-2 (human hepatoma cell) and MGC-803 (human gastric cancer cell), was evaluated by thiazole blue (MTT) method. The results showed that most of the compounds had specific antiproliferative activity against PC-3. Among them, N-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)-1-isopropyl-1H-in- doleazole-5-carboxyamide (8a) and N-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)-1-isopropyl-1H-indoleazole-6-formamide (14a) possess strong antitumor activity against PC-3 with IC₅₀ values of 6.21 and 6.43 μmol/L, respectively. It provides a new idea for the research of anti-tumor drugs for prostate cancer.

Key words: indazole, cancer, antiproliferative activity, prostatic cancer

引用此文

曹亚权, 杨莹雪, 翟洪进, 王锦, 张烁, 王焕焕, 杨璞, 吴春丽. 新型5位与6位取代的吲唑类衍生物的合成及抗肿瘤活性研究[J]. 有机化学, 2022, 42(2): 590-599.

Yaquan Cao, Yingxue Yang, Hongjin Zhai, Jin Wang, Shuo Zhang, Huanhuan Wang, Pu Yang, Chunli Wu. Synthesis and Antitumor Activity of Novel 5- and 6-Substituted Indazole Derivatives[J]. Chinese Journal of Organic Chemistry, 2022, 42(2): 590-599.

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Compound	R	IC₅₀^a/(μmol•L^–1)
Compound	R	PC-3	MCF-7	HepG-2	MGC-803
7a	H	30.67±1.63	>40	>40	>40
7b	2,4-(CH₃)₂	>40	>40	>40	>40
7c	3,4-(CH₃)₂	>40	>40	>40	>40
7d	4-I	39.63±1.21	>40	>40	>40
7e	4-F	38.72±0.96	>40	>40	>40
7f	3-Br	36.21±0.87	>40	>40	>40
7g	3-F	38.14±1.03	>40	>40	>40
7h	4-NO₂	>40	>40	>40	>40
7i	4-CH₃	36.98±1.63	>40	>40	>40
7j	3-CH₃	34.55±1.14	26.12±0.78	>40	34.75±2.07
7k	2-CH₃	35.40±2.97	>40	>40	>40
7l	2-F	>40	>40	>40	>40
7m	4-CF₃	37.21±0.89	>40	>40	>40
7n	4-CH₂CH₃	31.05±0.95	>40	>40	>40
7o	4-OCH₃	>40	>40	>40	>40
8a	H	6.21±0.84	19.33±0.68	18.17±2.91	20.56±1.01
8b	4-CF₃	15.81±0.78	>40	>40	>40
8c	4-CN	9.53±0.62	19.26±1.23	30.04±1.89	20.06±1.80
8d	4-OCH₃	28.20±2.20	>40	>40	>40
8e	4-C(CH₃)₃	8.76±1.98	>40	>40	>40
5-Fu^b	—	8.41±0.92	15.14±0.44	11.68±0.48	10.14±0.89

Compound	R	IC₅₀^a/(μmol•L^–1)
Compound	R	PC-3	MCF-7	HepG-2	MGC-803
7a	H	30.67±1.63	>40	>40	>40
7b	2,4-(CH₃)₂	>40	>40	>40	>40
7c	3,4-(CH₃)₂	>40	>40	>40	>40
7d	4-I	39.63±1.21	>40	>40	>40
7e	4-F	38.72±0.96	>40	>40	>40
7f	3-Br	36.21±0.87	>40	>40	>40
7g	3-F	38.14±1.03	>40	>40	>40
7h	4-NO₂	>40	>40	>40	>40
7i	4-CH₃	36.98±1.63	>40	>40	>40
7j	3-CH₃	34.55±1.14	26.12±0.78	>40	34.75±2.07
7k	2-CH₃	35.40±2.97	>40	>40	>40
7l	2-F	>40	>40	>40	>40
7m	4-CF₃	37.21±0.89	>40	>40	>40
7n	4-CH₂CH₃	31.05±0.95	>40	>40	>40
7o	4-OCH₃	>40	>40	>40	>40
8a	H	6.21±0.84	19.33±0.68	18.17±2.91	20.56±1.01
8b	4-CF₃	15.81±0.78	>40	>40	>40
8c	4-CN	9.53±0.62	19.26±1.23	30.04±1.89	20.06±1.80
8d	4-OCH₃	28.20±2.20	>40	>40	>40
8e	4-C(CH₃)₃	8.76±1.98	>40	>40	>40
5-Fu^b	—	8.41±0.92	15.14±0.44	11.68±0.48	10.14±0.89

Compound	R	IC₅₀^a/(μmol•L^–1)
Compound	R	PC-3	MCF-7	HepG-2	MGC-803
13a	H	30.25±1.36	>40	>40	>40
13b	2,4-(CH₃)₂	>40	>40	>40	>40
13c	3,4-(CH₃)₂	>40	>40	>40	>40
13d	4-I	38.37±0.89	>40	>40	>40
13e	4-F	38.67±0.67	>40	>40	>40
13f	3-Br	31.51±1.76	>40	>40	>40
13g	3-F	37.69±0.96	>40	>40	>40
13h	4-NO₂	>40	>40	>40	>40
13i	4-CH₃	32.05±1.35	>40	>40	>40
13j	3-CH₃	31.65±1.08	>40	>40	>40
13k	2-CH₃	30.15±1.25	>40	>40	>40
13l	2-F	>40	>40	>40	>40
13m	4-CF₃	36.28±0.87	>40	>40	>40
13n	4-CH₂CH₃	30.26±0.58	>40	>40	>40
13o	4-OCH₃	>40	>40	>40	>40
14a	H	6.43±0.80	11.19±0.40	12.72±0.60	14.41±2.12
14b	4-CF₃	21.90±1.69	31.91±1.18	30.99±0.99	39.92±1.63
14c	4-CN	11.16±1.76	32.28±0.79	24.71±3.90	33.06±2.68
14d	4-OCH₃	34.74±1.27	>40	>40	>40
14e	4--C(CH₃)₃	12.82±0.71	>40	>40	>40
5-Fu^b	—	8.41±0.92	15.14±0.44	11.68±0.48	10.14±0.89

Compound	R	IC₅₀^a/(μmol•L^–1)
Compound	R	PC-3	MCF-7	HepG-2	MGC-803
13a	H	30.25±1.36	>40	>40	>40
13b	2,4-(CH₃)₂	>40	>40	>40	>40
13c	3,4-(CH₃)₂	>40	>40	>40	>40
13d	4-I	38.37±0.89	>40	>40	>40
13e	4-F	38.67±0.67	>40	>40	>40
13f	3-Br	31.51±1.76	>40	>40	>40
13g	3-F	37.69±0.96	>40	>40	>40
13h	4-NO₂	>40	>40	>40	>40
13i	4-CH₃	32.05±1.35	>40	>40	>40
13j	3-CH₃	31.65±1.08	>40	>40	>40
13k	2-CH₃	30.15±1.25	>40	>40	>40
13l	2-F	>40	>40	>40	>40
13m	4-CF₃	36.28±0.87	>40	>40	>40
13n	4-CH₂CH₃	30.26±0.58	>40	>40	>40
13o	4-OCH₃	>40	>40	>40	>40
14a	H	6.43±0.80	11.19±0.40	12.72±0.60	14.41±2.12
14b	4-CF₃	21.90±1.69	31.91±1.18	30.99±0.99	39.92±1.63
14c	4-CN	11.16±1.76	32.28±0.79	24.71±3.90	33.06±2.68
14d	4-OCH₃	34.74±1.27	>40	>40	>40
14e	4--C(CH₃)₃	12.82±0.71	>40	>40	>40
5-Fu^b	—	8.41±0.92	15.14±0.44	11.68±0.48	10.14±0.89

Compd.	IC₅₀^a/(μmol•L^–1)		Active ratio
Compd.	PC-3	WPYM-1	WPYM-1/PC-3
8a	6.21±0.84	27.07±1.36	4.35
14a	6.43±0.80	23.57±1.77	3.67