Synthesis of Novel Camphor Sulfamoxime Ether Derivatives and Its Application in Antitumor Activity

doi:10.6023/cjoc202009050

Abstract

Based on the combination principle in drug design, a series of camphor sulfamoxime ether derivatives were designed and synthesized with (+)-10-camphorsulfonic acid as the staring materials via acyl chlorination, acyl amidation and condensation. The target compounds were characterized by ¹H NMR, ¹³C NMR and HRMS spectra. In addition, the antiproliferative effects of compounds were evaluated on a panel of human adherent cell lines (A549, Hela, MCF-7 and LO2) by means of methyl thiazolyl tetrazolium (MTT) assays. Noticeably, (+)-1-(2-((benzyloxy)imino)-7,7-dimethylbicyclo[2.2.1]-heptan- 1-yl)-N-(3-(trifluoromethyl)phenyl)methanesulfonamide (4r) possessed excellent antiproliferative against A549 (6.75 μmol? L ^–1), Hela (7.93 μmol?L ^–1) and MCF-7 (4.51 μmol?L ^–1). Flow cytometry was used to detect cell cycle progression and apoptosis, and morphological change of apoptosis was observed by Hoechst 33258 staining. Levels of reactive oxygen specy (ROS) and mitochondrial membrane potential were measured by DCFH-DA and JC-1, respectively. These results indicated that compound 4r could cause cell cycle arrest at G0/G1 phase and triggered apoptosis in MCF-7 cells. Furthermore, 4r could induce the accumulation of ROS and mitochondrial disruption. Taken together, compound 4r could be a potential anticancer drug candidate.

Key words: camphor sulfamoxime ether, antitumor activity, G0/G1 phase arrest, apoptosis

Cite this article

Yuxun Zhao, Yunyun Wang, Chenglong Zhang, Xu Xu, Shifa Wang. Synthesis of Novel Camphor Sulfamoxime Ether Derivatives and Its Application in Antitumor Activity[J]. Chinese Journal of Organic Chemistry, 2021, 41(3): 1224-1233.

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Fig. & Tab. 7

Figure 1. Chemical structures of oxime ethers and their derivatives

Scheme 1. Synthesis of compounds 4a~4r

Compd.	IC₅₀/(μmol?L^–1)
Compd.	A-549	Hela	MCF-7	LO2
4a	27.54±0.04	>50	>50	>50
4b	10.55±0.09	18.93±0.03	11.97±0.04	45±0.13
4c	10.17±0.02	7.69±0.06	12.43±0.08	>50
4d	14.80±0.13	>50	>50	>50
4e	12.63±0.06	13.59±0.12	18.96±0.04	42.18±0.07
4f	7.50±0.06	49.99±0.03	18.90±0.04	>50
4g	16.77±0.08	38.13±0.12	17.71±0.12	>50
4h	17.68±0.12	6.83±0.06	7.87±0.03	33.12±0.20
4i	8.29±0.06	6.69±0.06	8.50±0.07	46.70±0.20
4j	10.32±0.09	>50	>50	>50
4k	12.23±0.10	27.07±0.06	42.19±0.10	>50
4l	14.41±0.02	49.99±0.02	>50	>50
4m	13.69±0.10	>50	>50	31.33±0.12
4n	9.25±0.07	15.64±0.09	21.30±0.14	30.25±0.22
4o	6.80±0.06	10.04±0.04	27.82±0.06	43.15±0.16
4p	13.48±0.03	30.96±0.06	29.25±0.05	>50
4q	9.00±0.11	5.32±0.12	6.73±0.08	>50
4r	6.75±0.05	7.93±0.03	4.51±0.03	45.13±0.20
Etoposide	9.86±0.05	8.68±0.06	6.44±0.10	16.74±0.03

Table 1. Antiproliferative activities of compounds 4a~4r

Figure 2. Cell cycle analysis of compound 4r in MCF-7 cells (a) Cell cycle distribution upon treatment with compound 4r at different concentrations (0, 2.5, 5, 10 μmol?L –1) for 24 h in MCF-7 cells; (b) The statistical analysis of MCF-7 cells in the different phases of cell cycle was presented

Figure 3. Cell apoptosis analysis of compound 4r in MCF-7 cells (a) Hoechst 33258 staining of MCF-7 cells treated with 0, 2.5, 5 and 10 μmol?L –1 of compound 4r for 24 h and fluorescence was observed by confocal microscopy; (b) cell apoptosis rate upon treatment with different concentrations of compound 4r for 24 h in MCF-7 cells; (c) graphical representation of effect of compound 4r on cell apoptosis

Figure 4. ROS production uantified by DCFH-DA fluorescence probe Image observations were carried out by fluorescence microscopy

Figure 5. ΔΨm quantified by using the JC-1 JC-1 staining of MCF-7 cells treated with 0, 2.5, 5 and 10 μmol?L –1 of compound 4r for 24 h and images were acquired by confocal microscopy

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