β-咔啉-苯并咪唑偶联物的合成及抗肿瘤活性研究

doi:10.6023/cjoc202110025

摘要/Abstract

为进一步发现具有更好药理活性的新型β-咔啉类抗肿瘤药物, 以L-色氨酸和不同种类的醛为原料设计并合成了一系列具有不同取代基的1,9-二取代-β-咔啉-苯并咪唑偶联物. 采用噻唑蓝(MTT)法评估了目标化合物对肺癌(A549)、胃癌(BGC-823)、结肠癌(CT-26)、肝癌(Bel-7402)和乳腺癌(MCF-7)等五种肿瘤细胞株的体外抗肿瘤活性, 讨论了β-咔啉环1位和9位取代基对抗肿瘤活性的影响. 结果显示大多数目标化合物表现出广谱的抗肿瘤活性, 获得了初步的构效关系. 特别是化合物5s, 在β-咔啉环9位具有苄基且苯并咪唑环上具有三氟甲基取代, 对MCF-7细胞株具有最好的抗肿瘤活性, 其IC₅₀值为(4.9±0.3) μmol/L, 抗肿瘤活性明显优于阳性对照药顺铂. 化合物5c和5q对测试的3株肿瘤细胞都表现出良好的活性且IC₅₀值小于10 μmol/L; 细胞划痕实验结果表明这两个化合物对A549细胞横向迁移能力有一定的抑制效果

关键词: β-咔啉, 苯并咪唑, 抗肿瘤, 构效关系

In a continuing effort to develop novel β-carboline derivatives endowed with better pharmacological profiles, a series of 1,9-disubstituted β-carboline-benzimidazole hybrids with various substituents were designed and synthesized from L-tryptophan and aldehydes. The target compounds were subjected to antitumor screening against five different cancer cell lines, namely, A549 (lung carcinoma), BGC-823 (gastric carcinoma), CT-26 (murine colon carcinoma), Bel-7402 (liver carcinoma), and MCF-7 (breast carcinoma), using standard methyl thiazolyl tetrazolium (MTT) assay. The structure-activity relationships (SARs) of the conjugates with different substituents at positions 1 and 9 in β-carbolines were also analyzed. The obtained results showed that most conjugates exhibited good cytotoxic activity against more than one cancer cell line. In particular, compound 5s with a benzyl group at position-9 and a trifluoromethyl substituent on the benzimidazole ring had the highest activity against MCF-7 cells (IC₅₀ value of 4.9±0.3 μmol/L). Compounds 5c and 5q displayed significant cytotoxicity against three tumor cell lines, with IC₅₀ values lower than 10 μmol/L. Moreover, these two compounds could moderately reduce the number of migrated cells at concentrations of 2.5~10 μg•mL^–1.

Key words: β-carboline, benzimidazole, antitumor, structure-activity relationships

引用此文

朱思玉, 霍新玉, 马芹, 陈伟, 张洁, 郭亮. β-咔啉-苯并咪唑偶联物的合成及抗肿瘤活性研究[J]. 有机化学, 2022, 42(4): 1129-1135.

Siyu Zhu, Xinyu Huo, Qin Ma, Wei Chen, Jie Zhang, Liang Guo. Design, Synthesis, and Antitumor Activity of β-Carboline-Benzimidazole Hybrids[J]. Chinese Journal of Organic Chemistry, 2022, 42(4): 1129-1135.

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Compd.	R¹	R⁹	R	X	IC₅₀/(μmol•L^–1)±SD^a
Compd.	R¹	R⁹	R	X	A549	BGC-823	CT-26	Bel-7402	MCF-7
5a	H	n-Butyl	H	CH	32.1±2.8	16.1±1.4	17.2±1.3	13.3±1.1	12.7±0.9
5b	H	Benzyl	H	CH	9.7±0.7	17.5±1.6	13.8±1.1	15.6±1.3	16.1±1.2
5c	H	4-Fluorobenzyl	H	CH	8.6±0.6	7.6±0.7	16.4±1.3	7.4±0.7	13.2±1.1
5d	H	3-Phenylpropyl	H	CH	15.3±1.2	7.4±0.5	11.6±0.7	14.6±1.1	12.3±0.9
5e	CH₃	n-Butyl	H	CH	17.4±1.5	9.9±0.8	15.8±1.3	15.5±1.2	17.3±1.4
5f	CH₃	Benzyl	H	CH	10.7±0.9	17.4±1.5	13.1±1.2	18.9±1.7	14.3±1.2
5g	CH(CH₃)₂	n-Butyl	H	CH	24.7±2.1	14.8±1.2	17.2±1.4	17.8±1.2	16.9±1.5
5h	CH(CH₃)₂	Benzyl	H	CH	19.2±1.8	12.9±1.2	15.6±1.4	16.3±1.5	18.5±1.6
5i	C₆H₅	Benzyl	H	CH	9.4±0.9	12.8±1.2	10.2±0.8	22.6±1.5	13.8±1.1
5j	C₆H₄(o-Cl)	n-Butyl	H	CH	9.5±0.8	19.2±1.4	17.4±1.2	13.4±1.1	8.9±0.7
5k	C₆H₄(p-OCH₃)	Benzyl	H	CH	13.7±0.8	8.9±0.6	16.5±1.3	10.6±0.9	12.4±0.9
5l	3-Pyridyl	n-Butyl	H	CH	15.3±1.2	10.1±0.8	26.2±1.7	15.3±1.2	14.9±1.1
5m	2-Thienyl	Benzyl	H	CH	9.8±0.7	9.5±0.9	12.2±1.1	11.5±0.8	16.9±1.2
5n	H	n-Butyl	H	N	14.7±1.2	7.5±0.5	18.6±1.1	17.8±1.4	23.9±1.7
5o	H	Benzyl	H	N	21.2±1.9	24.7±2.1	32.3±2.5	21.1±1.8	12.4±1.1
5p	H	n-Butyl	OCH₃	CH	14.6±1.3	24.3±1.9	17.3±1.6	27.1±1.9	25.7±1.6
5q	H	n-Butyl	CF₃	CH	8.7±0.7	14.8±1.2	12.3±0.9	9.4±0.7	8.6±0.5
5r	H	Benzyl	OCH₃	CH	14.5±1.2	6.2±0.4	19.1±0.7	21.4±1.8	33.1±2.3
5s	H	Benzyl	CF₃	CH	10.1±0.6	14.3±0.8	18.3±0.5	10.1±0.7	4.9±0.3
Cisplatin					15.8±2.4	8.4±0.7	4.2±0.7	15.4±1.9	10.5±2.3

Compd.	R¹	R⁹	R	X	IC₅₀/(μmol•L^–1)±SD^a
Compd.	R¹	R⁹	R	X	A549	BGC-823	CT-26	Bel-7402	MCF-7
5a	H	n-Butyl	H	CH	32.1±2.8	16.1±1.4	17.2±1.3	13.3±1.1	12.7±0.9
5b	H	Benzyl	H	CH	9.7±0.7	17.5±1.6	13.8±1.1	15.6±1.3	16.1±1.2
5c	H	4-Fluorobenzyl	H	CH	8.6±0.6	7.6±0.7	16.4±1.3	7.4±0.7	13.2±1.1
5d	H	3-Phenylpropyl	H	CH	15.3±1.2	7.4±0.5	11.6±0.7	14.6±1.1	12.3±0.9
5e	CH₃	n-Butyl	H	CH	17.4±1.5	9.9±0.8	15.8±1.3	15.5±1.2	17.3±1.4
5f	CH₃	Benzyl	H	CH	10.7±0.9	17.4±1.5	13.1±1.2	18.9±1.7	14.3±1.2
5g	CH(CH₃)₂	n-Butyl	H	CH	24.7±2.1	14.8±1.2	17.2±1.4	17.8±1.2	16.9±1.5
5h	CH(CH₃)₂	Benzyl	H	CH	19.2±1.8	12.9±1.2	15.6±1.4	16.3±1.5	18.5±1.6
5i	C₆H₅	Benzyl	H	CH	9.4±0.9	12.8±1.2	10.2±0.8	22.6±1.5	13.8±1.1
5j	C₆H₄(o-Cl)	n-Butyl	H	CH	9.5±0.8	19.2±1.4	17.4±1.2	13.4±1.1	8.9±0.7
5k	C₆H₄(p-OCH₃)	Benzyl	H	CH	13.7±0.8	8.9±0.6	16.5±1.3	10.6±0.9	12.4±0.9
5l	3-Pyridyl	n-Butyl	H	CH	15.3±1.2	10.1±0.8	26.2±1.7	15.3±1.2	14.9±1.1
5m	2-Thienyl	Benzyl	H	CH	9.8±0.7	9.5±0.9	12.2±1.1	11.5±0.8	16.9±1.2
5n	H	n-Butyl	H	N	14.7±1.2	7.5±0.5	18.6±1.1	17.8±1.4	23.9±1.7
5o	H	Benzyl	H	N	21.2±1.9	24.7±2.1	32.3±2.5	21.1±1.8	12.4±1.1
5p	H	n-Butyl	OCH₃	CH	14.6±1.3	24.3±1.9	17.3±1.6	27.1±1.9	25.7±1.6
5q	H	n-Butyl	CF₃	CH	8.7±0.7	14.8±1.2	12.3±0.9	9.4±0.7	8.6±0.5
5r	H	Benzyl	OCH₃	CH	14.5±1.2	6.2±0.4	19.1±0.7	21.4±1.8	33.1±2.3
5s	H	Benzyl	CF₃	CH	10.1±0.6	14.3±0.8	18.3±0.5	10.1±0.7	4.9±0.3
Cisplatin					15.8±2.4	8.4±0.7	4.2±0.7	15.4±1.9	10.5±2.3