Synthesis and Antitumor Activities of Novel Organic Sulfur (Selenium) Tegafur Derivatives

doi:10.6023/cjoc202012047

Chinese Journal of Organic Chemistry ›› 2021, Vol. 41 ›› Issue (7): 2723-2734.DOI: 10.6023/cjoc202012047 Previous Articles Next Articles

ARTICLES

新型有机硫(硒)替加氟衍生物的合成及抗肿瘤活性研究

李宁波^a^,^b^,^c^,^*(), 续立^a, 马榕^a, 范琪^a, 李波^b, 乔洁^a^,^b, 郭睿^a^,^c^,^*(), 许新华^d

a 山西医科大学生物化学与分子生物学教研室山西太原 030001
b 山西医科大学医用化学教研室山西太原 030001
c 山西医科大学细胞生理学教育部重点实验室山西太原 030001
d 湖南大学化学化工学院长沙 410082

收稿日期:2020-12-28 修回日期:2021-03-30 发布日期:2021-04-16
通讯作者: 李宁波, 郭睿
基金资助:
国家自然科学基金(21802093); 山西省高等学校科技创新(2019L0408); 山西医科大学博士启动基金(03201501)

Synthesis and Antitumor Activities of Novel Organic Sulfur (Selenium) Tegafur Derivatives

Ningbo Li^a^,^b^,^c(), Li Xu^a, Rong Ma^a, Qi Fan^a, Bo Li^b, Jie Qiao^a^,^b, Rui Guo^a^,^c(), Xinhua Xu^d

a Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan, Shanxi 030001
b Department of Chemistry, Shanxi Medical University, Taiyuan, Shanxi 030001
c Key Laboratory of Cellular Physiology, Shanxi Medical University, Ministry of Education, Taiyuan, Shanxi 030001
d College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082

Received:2020-12-28 Revised:2021-03-30 Published:2021-04-16
Contact: Ningbo Li, Rui Guo
Supported by:
National Natural Science Foundation of China(21802093); Scientific and Technological Innovation Programs of Higher Education Institutions in Shanxi Province(2019L0408); PhD Start-up Foundation of Shanxi Medical University(03201501)

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Abstract

Tegafur, as a raw material, reacted with chloroalkyl alcohols to give the intermediateN-hydroxyalkyl tegafur, then which reacted withp-toluenesulfonyl chloride to obtain tegafluoroalkyl sulfonate. A series of novel aryl (N³-tegafluoroalkyl) thio- and seleno-ether derivatives were efficiently synthesized by the reaction of tegafluoroalkyl sulfonate with diaryl disulfides or diselenides under binuclear titanium(IV) salophen perfluorobutanesulfonate/zinc catalytic system. Their structures of the target products were confirmed by¹H NMR,¹³C NMR and HRMS. Their antitumor activities were evaluated by colorectal carcinoma HCT116 cells and gastric carcinoma SGC-7901 cells. The preliminary bioassay results showed that most target compounds had more antitumor activities than tegafur. Moreover, HCT116 cells staining experiments (DAPI) and quantitative determination by flow cytometry indicated that the growth inhibition was associated with the induction of apoptosis. In addition, organic sulfur (selenium) tegafur derivatives had lower toxicity than tegafur on human embryonic kidney HEK 293 cells.

Key words: tegafur, diaryl disulfides (diselenides), unsymmetrical sulfides (selenides), antitumor activity, apoptosis

Cite this article

Ningbo Li, Li Xu, Rong Ma, Qi Fan, Bo Li, Jie Qiao, Rui Guo, Xinhua Xu. Synthesis and Antitumor Activities of Novel Organic Sulfur (Selenium) Tegafur Derivatives[J]. Chinese Journal of Organic Chemistry, 2021, 41(7): 2723-2734.

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References 27

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Entry	Cat./mol%	Zn dust/ mmol	Solvent	Time/h	Yield^b/%
1	5	0	THF	12	0
2	0	1	THF	12	0
3	5	1	THF	4	82
4	5	1.2	THF	4	94
5	7	1.2	THF	4	93
6	5	1.5	THF	4	94
6	5	1.2	THF	1	94
7	5	1.2	THF	0.5	73
8	5	1.2	CH₃CN	1	72
9	5	1.2	CH₂Cl₂	1	47
10	5	1.2	DMF	1	68
11	5	1.2	Toluene	1	26

Entry	Cat./mol%	Zn dust/ mmol	Solvent	Time/h	Yield^b/%
1	5	0	THF	12	0
2	0	1	THF	12	0
3	5	1	THF	4	82
4	5	1.2	THF	4	94
5	7	1.2	THF	4	93
6	5	1.5	THF	4	94
6	5	1.2	THF	1	94
7	5	1.2	THF	0.5	73
8	5	1.2	CH₃CN	1	72
9	5	1.2	CH₂Cl₂	1	47
10	5	1.2	DMF	1	68
11	5	1.2	Toluene	1	26

Compd.	IC₅₀+SD/(μmol•L^–1)
Compd.	HCT-116	SGC-7901
Tegafur	861.13±15.34	1000.42±10.89
5a	518.74±4.38	610.82±6.86
5b	223.15±2.09	445.23±4.70
5c	389.53±3.79	398.80±4.52
5d	217.06±1.74	242.16±2.10
5e	994.99±4.57	883.61±1.69
5f	176.72±3.16	265.08±2.68
5g	447.89±3.94	458.44±3.15
5h	1058.44±6.91	501.28±7.84
5i	246.49±12.71	238.43±1.53
5j	729.13±3.75	348.14±6.50
5k	142.07±7.77	240.11±4.66
5l	224.91±4.88	274.50±3.32
5m	252.36±3.88	290.93±6.12
5n	308.94±5.90	258.75±2.19
5o	601.26±5.80	1115.76±4.05
5p	428.59±3.78	744.04±2.73
5q	352.59±2.62	771.33±5.50
5r	290.06±3.49	604.25±4.03
5s	135.34±1.88	226.97±3.86
5t	392.60±2.03	405.85±3.91
5u	239.64±2.40	235.93±4.34
5v	223.40±2.97	197.35±2.16
5w	224.85±4.32	230.69±3.62
5x	200.62±2.92	247.33±3.43
5y	198.56±3.30	335.06±5.65

Compd.	IC₅₀+SD/(μmol•L^–1)
Compd.	HCT-116	SGC-7901
Tegafur	861.13±15.34	1000.42±10.89
5a	518.74±4.38	610.82±6.86
5b	223.15±2.09	445.23±4.70
5c	389.53±3.79	398.80±4.52
5d	217.06±1.74	242.16±2.10
5e	994.99±4.57	883.61±1.69
5f	176.72±3.16	265.08±2.68
5g	447.89±3.94	458.44±3.15
5h	1058.44±6.91	501.28±7.84
5i	246.49±12.71	238.43±1.53
5j	729.13±3.75	348.14±6.50
5k	142.07±7.77	240.11±4.66
5l	224.91±4.88	274.50±3.32
5m	252.36±3.88	290.93±6.12
5n	308.94±5.90	258.75±2.19
5o	601.26±5.80	1115.76±4.05
5p	428.59±3.78	744.04±2.73
5q	352.59±2.62	771.33±5.50
5r	290.06±3.49	604.25±4.03
5s	135.34±1.88	226.97±3.86
5t	392.60±2.03	405.85±3.91
5u	239.64±2.40	235.93±4.34
5v	223.40±2.97	197.35±2.16
5w	224.85±4.32	230.69±3.62
5x	200.62±2.92	247.33±3.43
5y	198.56±3.30	335.06±5.65

新型有机硫(硒)替加氟衍生物的合成及抗肿瘤活性研究

Synthesis and Antitumor Activities of Novel Organic Sulfur (Selenium) Tegafur Derivatives

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