Synthesis and Anticancer Activity of 4-Phenoxyquinoline Derivatives Bearing Semicarbazone Moiety as c-Met Inhibitors

doi:10.7503/cjcu20240439

Abstract

Abstract:

Thirteen novel 4-phenoxyquinoline derivatives bearing semicarbazone moiety were successfully designed and synthesized based on the structural characteristics of 4-phenoxyquinoline small molecule type II c-Met kinase inhibitors. The in vitro inhibitory activities of all the target compounds against c-Met kinase were evaluated using mobility shift assay. The in vitro antiproliferative activities of the target compounds against A549， PC-3， AGS and MKN45 cells were evaluated using MTT-based assay. Most of the target compounds showed excellent inhibitory activities against c-Met kinase and all the tested cancer cell lines. Among them， compounds 6f（c-Met： IC₅₀=14.50 nmol/L） and 6k（c-Met： IC₅₀=15.68 nmol/L） exhibited excellent inhibition activity of against c-Met kinase. The IC₅₀ values of 6f for A549， PC-3， AGS and MKN-45 cells were 0.93， 7.81， 12.88， and 2.58 μmol/L， respectively. The IC₅₀ values of 6k for A549， PC-3， AGS and MKN45 cells were 0.67， 6.60， 3.04， and 0.88 μmol/L， respectively. Further studies on the anti-tumor mechanism indicated that compound 6k induced MKN45 and A549 cells apoptosis， and inhibited the migration ability of MKN45 and A549 cells.

Key words: Drug molecular design, c-Met inhibitor, 4-Phenoxyquinoline, Semicarbazone, Anticancer activity

CLC Number:

O626.3

TrendMD:

WU Shuang, LIN Siyu, LI Nan, LIN Yihan, DING Shi, CHEN Ye, LIU Ju, SHEN Jiwei. Synthesis and Anticancer Activity of 4-Phenoxyquinoline Derivatives Bearing Semicarbazone Moiety as c-Met Inhibitors[J]. Chem. J. Chinese Universities, 2025, 46(4): 20240439.

Figures/Tables 4

References 25

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Compd.	R	IC₅₀^a /（nmol‧L^‒1）	IC₅₀^a /（μmol‧L^‒1）
Compd.	R	c⁃Met	A549	PC⁃3	AGS	MKN45
6a	4⁃F	48.71 ± 2.68	14.41 ± 0.29	5.34 ± 0.51	6.65 ± 0.48	1.79 ± 1.46
6b	4⁃Cl	>5000	14.86 ± 0.43	1.13 ± 0.09	3.77 ± 0.36	1.98 ± 0.19
6c	4⁃Br	>5000	9.57 ± 0.35	3.19 ± 0.27	2.63 ± 0.19	6.03 ± 0.46
6d	4⁃CF₃	374.26 ± 0.63	2.31 ± 0.11	8.12 ± 0.84	3.67 ± 0.38	0.98 ± 0.10
6e	4⁃N（CH₃）₂	134.35 ± 3.56	1.81 ± 0.12	0.96 ± 0.09	5.39 ± 0.31	3.22 ± 0.21
6f	4⁃SO₂CH₃	14.50 ± 0.40	0.93 ± 0.06	7.81 ± 0.83	12.88 ± 1.78	2.58 ± 0.16
6g	3，4⁃diF	51.54 ± 0.32	7.14 ± 0.76	7.45 ± 0.68	6.00 ± 0.54	3.01 ± 0.37
6h	2⁃Cl⁃4⁃F	>5000	14.40 ± 1.49	2.82 ± 0.25	22.94 ± 1.02	9.78 ± 0.43
6i	2，3⁃diCl	>5000	46.61 ± 3.53	3.23 ± 0.12	26.36 ± 2.56	6.61 ± 0.57
6j	3，4⁃diOCH₃	84.31 ± 0.63	7.47 ± 0.54	12.62 ± 1.51	4.89 ± 0.28	2.58 ± 0.14
6k	3⁃OH⁃4⁃OCH₃	15.68 ± 0.28	0.67 ± 0.06	6.60 ± 0.48	13.04 ± 1.17	0.88 ± 0.06
6l	2，4⁃diOH	22.46 ± 1.03	4.29 ± 0.19	4.87 ± 0.35	9.68 ± 0.62	1.42 ± 0.12
6m	3，4，5⁃riOCH₃	98.79 ± 1.69	4.31 ± 0.22	5.32 ± 0.27	3.67 ± 0.14	2.13 ± 0.17
Foretinib ^b	—	1.53 ± 0.13	1.12 ± 0.09	0.51 ± 0.03	0.97 ± 0.06	0.06 ± 0.003

Compd.	R	IC₅₀^a /（nmol‧L^‒1）	IC₅₀^a /（μmol‧L^‒1）
Compd.	R	c⁃Met	A549	PC⁃3	AGS	MKN45
6a	4⁃F	48.71 ± 2.68	14.41 ± 0.29	5.34 ± 0.51	6.65 ± 0.48	1.79 ± 1.46
6b	4⁃Cl	>5000	14.86 ± 0.43	1.13 ± 0.09	3.77 ± 0.36	1.98 ± 0.19
6c	4⁃Br	>5000	9.57 ± 0.35	3.19 ± 0.27	2.63 ± 0.19	6.03 ± 0.46
6d	4⁃CF₃	374.26 ± 0.63	2.31 ± 0.11	8.12 ± 0.84	3.67 ± 0.38	0.98 ± 0.10
6e	4⁃N（CH₃）₂	134.35 ± 3.56	1.81 ± 0.12	0.96 ± 0.09	5.39 ± 0.31	3.22 ± 0.21
6f	4⁃SO₂CH₃	14.50 ± 0.40	0.93 ± 0.06	7.81 ± 0.83	12.88 ± 1.78	2.58 ± 0.16
6g	3，4⁃diF	51.54 ± 0.32	7.14 ± 0.76	7.45 ± 0.68	6.00 ± 0.54	3.01 ± 0.37
6h	2⁃Cl⁃4⁃F	>5000	14.40 ± 1.49	2.82 ± 0.25	22.94 ± 1.02	9.78 ± 0.43
6i	2，3⁃diCl	>5000	46.61 ± 3.53	3.23 ± 0.12	26.36 ± 2.56	6.61 ± 0.57
6j	3，4⁃diOCH₃	84.31 ± 0.63	7.47 ± 0.54	12.62 ± 1.51	4.89 ± 0.28	2.58 ± 0.14
6k	3⁃OH⁃4⁃OCH₃	15.68 ± 0.28	0.67 ± 0.06	6.60 ± 0.48	13.04 ± 1.17	0.88 ± 0.06
6l	2，4⁃diOH	22.46 ± 1.03	4.29 ± 0.19	4.87 ± 0.35	9.68 ± 0.62	1.42 ± 0.12
6m	3，4，5⁃riOCH₃	98.79 ± 1.69	4.31 ± 0.22	5.32 ± 0.27	3.67 ± 0.14	2.13 ± 0.17
Foretinib ^b	—	1.53 ± 0.13	1.12 ± 0.09	0.51 ± 0.03	0.97 ± 0.06	0.06 ± 0.003

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