Design, Synthesis, and Antitumor Activity of β-Carboline-Benzimidazole Hybrids

doi:10.6023/cjoc202110025

Abstract

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

Cite this article

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

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