Synthesis and Evaluation in vitro of Dihydrothiophenopyridine-Chalcone Derivatives as Anticancer Activity Agents

doi:10.6023/cjoc202101014

Abstract

The amide intermediates 5a~5j were prepared by acylation, which used 2-thiopheneethylamine and several self-synthetic chalcone acids as starting materials. Then ten dihydrothiophenopyridine-chalcone derivatives 6a~6j which haven't been reported before were synthesized by Bischer-Napieralski cyclization reaction from the intermediates. In addition, two new thiophenopyridine-chalconone derivatives 7a and 7b were obtained by further dehydrogenation. The anti-cancer activity and safety in vitro of 11 kinds of cells were evaluated by methyl thiazolyl tetrazolium (MTT) assay. The results indicated that the compounds 6a (p-F), 6d (o-Br) and 6h (m-OCH₃) exerted better anticancer activity against HeLa and SGC-7901 cells than taxol. When treating cells for a short time (<4 h), 6j (3,4,5-(OCH₃)₃) showed strong anticancer activity against MCF-7 cancer cell but displayed little toxicity on normal breast cell MCF-10A. Hence, 6j deserves further research and exploitation.

Key words: dihydrothiophenopyridine-chalcone derivatives, anticancer activity, selectivity, drug uptake capacity

Cite this article

Xin Liu, Runmei Xu, Lin Wang, Yaxue Liu, Zhihao Chen, Wei Qin, Yushun Tian. Synthesis and Evaluation in vitro of Dihydrothiophenopyridine-Chalcone Derivatives as Anticancer Activity Agents[J]. Chinese Journal of Organic Chemistry, 2021, 41(9): 3550-3559.

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Compd.	R	IC₅₀/(µmol•L^–1)
Compd.	R	BEL-7402	HepG2	HCT116	A549	MGC-803	SGC-7901	AGS	MCF-7	MCF-10A	HeLa	L-02
3a	p-F	31.7±5.4	>100	10.7±2.2	>100	18.9±2.1	22.0±1.3	22.7±7.8	40.6±9.2	32.8±2.8	39.1±12.1	21.2±5.7
3b	p-Cl	>100	>100	>100	>100	>100	>100	>100	>100	>100	>100	>100
3c	p-H	14.3±3.4	>100	21.0±0.5	>100	>100	>100	32.3±1.4	24.1±0.4	47.4±4.6	35.3±2.3	27.1±1.6
3d	o-Br	25.8±3.3	94.3±5.1	8.63±2.1	>100	15.4±6.1	26.6±4.6	22.8±7.3	45.1±5.7	37.2±6.9	69.5±8.8	23.4±2.8
3e	m-Br	5.9±0.03	11.7±4.7	3.0±2.0	20.2±4.3	5.3±0.8	3.2±0.8	5.3±3.5	13.6±2.3	8.2±2.3	23.5±8.8	5.3±0.3
3f	p-Br	10.3±0.1	35.5±13.7	3.5±1.9	57.2±4.5	9.9±1.2	3.3±1.9	12.8±3.0	17.2±4.5	16.1±2.7	15.0±4.9	11.4±3.4
3g	p-CH₃	16.0±2.5	42.0±3.2	8.0±1.9	50.8±3.0	15.1±1.0	12.5±1.5	24.7±7.0	27.4±3.9	28.9±5.5	36.3±7.9	15.6±1.8
3h	m-OCH₃	23.6±2.7	44.5±15.4	7.2±0.9	>100	15.6±0.8	11.7±1.1	36.7±10.2	28.0±3.9	28.8±7.4	55.4±8.9	18.8±2.1
3i	p-OCH₃	12.3±3.1	89.6±0.4	6.4±3.2	>100	8.5±0.8	10.7±2.2	16.9±1.5	>100	51.1±5.7	42.6±8.0	7.5±1.7
3j	3,4,5-(OCH₃)₃	8.0±1.4	>100	>100	>100	11.0±1.4	>100	11.3±3.4	21.5±4.3	38.8±11.8	39.4±1.2	5.8±2.6
Taxol		0.09±0.02	0.94±0.03	0.03±0.01	0.44±0.02	0.06±0.01	>100	0.02±0.01	0.08±0.01	0.18±0.02	13.0±0.4	>100

Compd.	R	IC₅₀/(µmol•L^–1)
Compd.	R	BEL-7402	HepG2	HCT116	A549	MGC-803	SGC-7901	AGS	MCF-7	MCF-10A	HeLa	L-02
3a	p-F	31.7±5.4	>100	10.7±2.2	>100	18.9±2.1	22.0±1.3	22.7±7.8	40.6±9.2	32.8±2.8	39.1±12.1	21.2±5.7
3b	p-Cl	>100	>100	>100	>100	>100	>100	>100	>100	>100	>100	>100
3c	p-H	14.3±3.4	>100	21.0±0.5	>100	>100	>100	32.3±1.4	24.1±0.4	47.4±4.6	35.3±2.3	27.1±1.6
3d	o-Br	25.8±3.3	94.3±5.1	8.63±2.1	>100	15.4±6.1	26.6±4.6	22.8±7.3	45.1±5.7	37.2±6.9	69.5±8.8	23.4±2.8
3e	m-Br	5.9±0.03	11.7±4.7	3.0±2.0	20.2±4.3	5.3±0.8	3.2±0.8	5.3±3.5	13.6±2.3	8.2±2.3	23.5±8.8	5.3±0.3
3f	p-Br	10.3±0.1	35.5±13.7	3.5±1.9	57.2±4.5	9.9±1.2	3.3±1.9	12.8±3.0	17.2±4.5	16.1±2.7	15.0±4.9	11.4±3.4
3g	p-CH₃	16.0±2.5	42.0±3.2	8.0±1.9	50.8±3.0	15.1±1.0	12.5±1.5	24.7±7.0	27.4±3.9	28.9±5.5	36.3±7.9	15.6±1.8
3h	m-OCH₃	23.6±2.7	44.5±15.4	7.2±0.9	>100	15.6±0.8	11.7±1.1	36.7±10.2	28.0±3.9	28.8±7.4	55.4±8.9	18.8±2.1
3i	p-OCH₃	12.3±3.1	89.6±0.4	6.4±3.2	>100	8.5±0.8	10.7±2.2	16.9±1.5	>100	51.1±5.7	42.6±8.0	7.5±1.7
3j	3,4,5-(OCH₃)₃	8.0±1.4	>100	>100	>100	11.0±1.4	>100	11.3±3.4	21.5±4.3	38.8±11.8	39.4±1.2	5.8±2.6
Taxol		0.09±0.02	0.94±0.03	0.03±0.01	0.44±0.02	0.06±0.01	>100	0.02±0.01	0.08±0.01	0.18±0.02	13.0±0.4	>100

Compd.	R	IC₅₀/(µmol•L^–1)
Compd.	R	BEL-7402	HepG2	HCT116	A549	MGC-803	SGC-7901	AGS	MCF-7	MCF-10A	HeLa	L-02
6a	p-F	6.0±0.2	17.8±2.6	7.6±0.5	23.6±4.9	6.6±1.1	6.0±0.3	8.3±2.6	9.0±3.0	8.5±2.8	10.5±2.6	5.6±1.6
6b	p-Cl	11.0±0.4	>100	10.1±4.1	16.5±2.6	13.8±4.0	>100	11.4±1.4	17.8±0.7	13.7±5.0	28.9±11.3	15.7±1.1
6c	p-H	8.7±1.0	>100	11.8±2.8	18.3±9.7	14.3±2.1	15.1±6.7	10.4±7.6	6.40±1.3	17.9±4.0	19.4±2.3	11.3±2.8
6d	o-Br	3.8±4.8	15.6±0.3	5.1±0.5	20.2±3.5	3.6±1.7	6.7±0.03	5.7±2.5	10.2±1.4	7.6±1.2	10.9±5.6	6.9±1.7
6e	m-Br	5.9±2.9	54.5±31.2	6.5±2.4	20.7±1.1	14.7±5.1	18.3±1.7	24.3±5.6	14.1±5.7	7.4±2.2	13.9±5.6	7.2±3.2
6f	p-Br	>100	>100	5.2±2.1	>100	15.7±0.4	17.3±6.5	37.0±12.7	>100	>100	46.1±1.6	41.1±2.5
6g	p-CH₃	21.8±3.2	>100	9.3±1.3	26.5±5.1	3.4±2.0	8.2±0.2	28.7±8.2	15.1±3.5	20.3±11.7	15.2±4.0	14.9±6.3
6h	m-OCH₃	5.0±3.7	19.2±2.9	6.1±1.3	15.9±5.7	5.6±0.7	9.0±1.0	5.9±4.6	12.3±4.1	10.5±5.1	7.5±1.2	6.1±5.1
6i	p-OCH₃	24.4±4.9	>100	24.0±3.1	23.5±6.8	8.9±2.4	11.0±0.4	17.7±8.0	24.7±7.8	>100	21.8±1.5	11.0±0.7
6j	3,4,5-(OCH₃)₃	6.1±1.3	>100	4.9±1.7	10.9±9.2	6.4±0.5	>100	1.3±0.1	15.0±5.0	16.8±4.3	18.5±9.7	8.2±2.0
7a	p-F	4.5±0.1	>100	17.3±3.2	36.2±2.8	12.3±0.9	24.1±6.4	14.5±3.5	6.5±1.6	27.6±3.6	24.6±4.5	10.7±5.9
7b	p-Cl	62.9±1.0	>100	21.0±0.5	>100	>100	75.4±11.8	48.9±0.4	56.4±10.3	>100	>100	32.5±0.6
Taxol		0.09±0.02	0.94±0.03	0.03±0.01	0.44±0.02	0.06±0.01	>100	0.02±0.01	0.08±0.01	0.18±0.02	13.0±0.4	>100

Compd.	R	IC₅₀/(µmol•L^–1)
Compd.	R	BEL-7402	HepG2	HCT116	A549	MGC-803	SGC-7901	AGS	MCF-7	MCF-10A	HeLa	L-02
6a	p-F	6.0±0.2	17.8±2.6	7.6±0.5	23.6±4.9	6.6±1.1	6.0±0.3	8.3±2.6	9.0±3.0	8.5±2.8	10.5±2.6	5.6±1.6
6b	p-Cl	11.0±0.4	>100	10.1±4.1	16.5±2.6	13.8±4.0	>100	11.4±1.4	17.8±0.7	13.7±5.0	28.9±11.3	15.7±1.1
6c	p-H	8.7±1.0	>100	11.8±2.8	18.3±9.7	14.3±2.1	15.1±6.7	10.4±7.6	6.40±1.3	17.9±4.0	19.4±2.3	11.3±2.8
6d	o-Br	3.8±4.8	15.6±0.3	5.1±0.5	20.2±3.5	3.6±1.7	6.7±0.03	5.7±2.5	10.2±1.4	7.6±1.2	10.9±5.6	6.9±1.7
6e	m-Br	5.9±2.9	54.5±31.2	6.5±2.4	20.7±1.1	14.7±5.1	18.3±1.7	24.3±5.6	14.1±5.7	7.4±2.2	13.9±5.6	7.2±3.2
6f	p-Br	>100	>100	5.2±2.1	>100	15.7±0.4	17.3±6.5	37.0±12.7	>100	>100	46.1±1.6	41.1±2.5
6g	p-CH₃	21.8±3.2	>100	9.3±1.3	26.5±5.1	3.4±2.0	8.2±0.2	28.7±8.2	15.1±3.5	20.3±11.7	15.2±4.0	14.9±6.3
6h	m-OCH₃	5.0±3.7	19.2±2.9	6.1±1.3	15.9±5.7	5.6±0.7	9.0±1.0	5.9±4.6	12.3±4.1	10.5±5.1	7.5±1.2	6.1±5.1
6i	p-OCH₃	24.4±4.9	>100	24.0±3.1	23.5±6.8	8.9±2.4	11.0±0.4	17.7±8.0	24.7±7.8	>100	21.8±1.5	11.0±0.7
6j	3,4,5-(OCH₃)₃	6.1±1.3	>100	4.9±1.7	10.9±9.2	6.4±0.5	>100	1.3±0.1	15.0±5.0	16.8±4.3	18.5±9.7	8.2±2.0
7a	p-F	4.5±0.1	>100	17.3±3.2	36.2±2.8	12.3±0.9	24.1±6.4	14.5±3.5	6.5±1.6	27.6±3.6	24.6±4.5	10.7±5.9
7b	p-Cl	62.9±1.0	>100	21.0±0.5	>100	>100	75.4±11.8	48.9±0.4	56.4±10.3	>100	>100	32.5±0.6
Taxol		0.09±0.02	0.94±0.03	0.03±0.01	0.44±0.02	0.06±0.01	>100	0.02±0.01	0.08±0.01	0.18±0.02	13.0±0.4	>100

Compd.	R	m.p./℃	Yield/%
3a	p-H	212~213	61.8
3b	p-F	255~256	79.7
3c	p-Cl	259~260	95.3
3d	o-Br	232~233	83.9
3e	m-Br	206~207	74.7
3f	p-Br	246~247	77.3
3g	p-CH₃	242~243	81.9
3h	m-OCH₃	101~102	66.3
3i	p-OCH₃	224~226	84.6
3j	3,4,5-(OCH₃)₃	223~224	61.7

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