Synthesis and Antitumor Activity of Novel 3,3'-((4-Chloro-2H-thiochromen-3-yl)methylene)bis(1H-indole)-Like Topoisomerase II Inhibitors

doi:10.6023/cjoc202311023

Abstract

A series of 3,3'-((4-chloro-2H-thiochromen-3-yl)methylene)bis(1H-indole) analogues containing bisindole and benzothiopyran structures were designed and synthesized by docking and splicing groups with known bioactive structures. Antitumor assay against six tumor cell lines of the target compounds were screened and the results indicate that 3,3'-(4-chloro- 2H-thioene-3-yl)methylene)bis(5-methoxy-1H-indole) (5b), 3,3'-(4-chloro-7-methyl-2H-thioene-3-yl)methylene)bis(5-methyl- 1H-indole) (5f), and 3,3'-(4-chloro-7-methyl-2H-thioene-3-yl)methylene)bis(N-methyl-2-methylindole) (5g) showed good anti- proliferative activity against tumor cells. The results of topoisomerase inhibition assay showed that compounds 5b, 3,3'-(4-chloro-2H-thioene-3-yl)methylene)bis(6-cyano-1H-indole) (5c), 5f and 5g showed selective inhibitory activity against DNA topoisomerase II, while other compounds showed different levels of DNA topoisomerase II inhibition activity. The results of molecular docking studies indicated that compounds 5b and 5g had stable binding with DNA topoisomerase II, which had potential research value for antitumor drugs.

Key words: bisindole, antitumor, DNA topoisomerase II, molecular docking

Cite this article

Guochao Liang, Tingting Dong, Haiying Ji, Chunyan Wang, Yali Song, Wei Zhang. Synthesis and Antitumor Activity of Novel 3,3'-((4-Chloro-2H-thiochromen-3-yl)methylene)bis(1H-indole)-Like Topoisomerase II Inhibitors[J]. Chinese Journal of Organic Chemistry, 2024, 44(6): 1949-1956.

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Compd.	IC₅₀/(μmol•L^–1)
Compd.	HeLa	H446	U-937	MCF-7	SK-OV-3	HT-29
5a	16.5±1.2	17.6±3.2	12.7±1.1	17.7±2.8	18.6±2.1	19.8±1.9
5b	14.5±2.2	8.6±1.4	10.3±1.9	14.2±1.7	16.8±1.9	14.1±3.4
5c	22.4±2.7	18.8±2.0	11.9±2.4	10.5±2.2	15.4±1.6	12.2±2.3
5d	38.4±3.3	65.6±3.6	72.7±4.1	47.5±2.5	66.6±2.4	72.6±3.9
5e	20.5±1.5	28.9±1.4	21.4±2.1	65.1±4.2	41.5±2.7	25.3±3.2
5f	8.7±1.2	8.8±2.1	14.3±3.1	14.9±1.7	13.3±2.7	21.1±1.6
5g	10.6±2.3	12.8±1.4	10.5±1.7	7.4±1.8	14.7±3.6	12.7±2.3
5h	66.7±2.6	32.5±1.7	45.7±4.5	34.6±2.2	64.3±3.9	22.6±2.4
5i	45.2±3.6	37.8±3.1	35.2±2.8	29.5±3.3	56.2±4.2	36.6±3.6
5j	65.7±2.9	50.4±3.6	45.8±5.5	63.4±4.6	45.6±4.5	67.2±4.4
5k	36.4±6.3	62.1±6.4	76.8±4.8	68.4±2.2	45.7±3.1	53.1±3.7
5l	19.6±2.3	20.6±1.9	35.7±3.4	58.2±4.6	64.2±2.9	60.7±3.6
5m	72.5±4.3	48.4±3.4	32.4±2.1	54.0±5.2	62.4±3.2	43.2±4.2
VP-16	8.6±1.4	9.1±0.4	8.2±1.5	8.4±0.6	9.8±1.5	7.2±1.1
CPT	7.4±1.5	8.7±1.3	10.4±1.5	7.8±1.4	8.5±1.2	7.7±1.2

Compd.	IC₅₀/(μmol•L^–1)
Compd.	HeLa	H446	U-937	MCF-7	SK-OV-3	HT-29
5a	16.5±1.2	17.6±3.2	12.7±1.1	17.7±2.8	18.6±2.1	19.8±1.9
5b	14.5±2.2	8.6±1.4	10.3±1.9	14.2±1.7	16.8±1.9	14.1±3.4
5c	22.4±2.7	18.8±2.0	11.9±2.4	10.5±2.2	15.4±1.6	12.2±2.3
5d	38.4±3.3	65.6±3.6	72.7±4.1	47.5±2.5	66.6±2.4	72.6±3.9
5e	20.5±1.5	28.9±1.4	21.4±2.1	65.1±4.2	41.5±2.7	25.3±3.2
5f	8.7±1.2	8.8±2.1	14.3±3.1	14.9±1.7	13.3±2.7	21.1±1.6
5g	10.6±2.3	12.8±1.4	10.5±1.7	7.4±1.8	14.7±3.6	12.7±2.3
5h	66.7±2.6	32.5±1.7	45.7±4.5	34.6±2.2	64.3±3.9	22.6±2.4
5i	45.2±3.6	37.8±3.1	35.2±2.8	29.5±3.3	56.2±4.2	36.6±3.6
5j	65.7±2.9	50.4±3.6	45.8±5.5	63.4±4.6	45.6±4.5	67.2±4.4
5k	36.4±6.3	62.1±6.4	76.8±4.8	68.4±2.2	45.7±3.1	53.1±3.7
5l	19.6±2.3	20.6±1.9	35.7±3.4	58.2±4.6	64.2±2.9	60.7±3.6
5m	72.5±4.3	48.4±3.4	32.4±2.1	54.0±5.2	62.4±3.2	43.2±4.2
VP-16	8.6±1.4	9.1±0.4	8.2±1.5	8.4±0.6	9.8±1.5	7.2±1.1
CPT	7.4±1.5	8.7±1.3	10.4±1.5	7.8±1.4	8.5±1.2	7.7±1.2

新型3,3'-((4-氯-2H-硫色烯-3-基)亚甲基)双(1H-吲哚)类拓扑异构酶Ⅱ抑制剂的合成及抗肿瘤活性研究