Synthesis of Diethyl 2,5-Diaminothiophene-3,4-dicarboxylate Derivatives and Antitumor Activity Study

doi:10.6023/cjoc202210040

Chinese Journal of Organic Chemistry ›› 2023, Vol. 43 ›› Issue (7): 2543-2552.DOI: 10.6023/cjoc202210040 Previous Articles Next Articles

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2,5-二氨基噻吩-3,4-二羧酸二乙酯衍生物的合成及抗肿瘤活性研究

张维舒^a^,^b, 聂礼飞^a, Khurshed Bozorov^a^,^c, 阿吉艾克拜尔•艾萨^a^,^b, 赵江瑜^a^,^b^,^*()

^a中国科学院新疆理化技术研究所新疆特有药用资源利用重点实验室乌鲁木齐 830011
^b中国科学院大学北京 100049
^c撒马尔罕国立大学化学学院撒马尔罕乌兹别克斯坦 140104

收稿日期:2022-10-30 修回日期:2023-01-08 发布日期:2023-02-06
通讯作者: 赵江瑜
基金资助:
国家重点研发计划(2020YFE0205600)

Synthesis of Diethyl 2,5-Diaminothiophene-3,4-dicarboxylate Derivatives and Antitumor Activity Study

Weishu Zhang^a^,^b, Lifei Nie^a, Khurshed Bozorov^a^,^c, Haji Akber Aisa^a^,^b, Jiangyu Zhao^a^,^b()

^aState Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi 830011
^bUniversity of Chinese Academy of Sciences, Beijing 100049
^cFaculty of Chemistry, Samarkand State University, Samarkand, Uzbekistan 140104

Received:2022-10-30 Revised:2023-01-08 Published:2023-02-06
Contact: Jiangyu Zhao
Supported by:
National Key R&D Program of China(2020YFE0205600)

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Abstract

Based on the sulfur heterocyclic compound thiophene, thirty diethyl 2,5-diaminothiophene-3,4-dicarboxylate derivatives were designed and synthesized. The structures of all compounds were confirmed by ¹H NMR, ¹³C NMR and HRMS, and antiproliferative activities of the target compounds against four human cancer cell lines (HeLa, HT-29, A549 and HepG2) were evaluated by methyl thiazolyl tetrazolium (MTT) in vitro. The results showed that some compounds exhibited good anticancer activity. Especially, diethyl 2-(4-(trifluoromethoxy)benzamido-5-(5-nitrothiophen-2-yl)methylene-aminothiophene- 3,4-dicarboxylate (C25) possessed the best activity, whose IC₅₀ values were (0.35±0.07) and (0.66±0.09) μmol/L against HT-29 and A549, respectively; diethyl 2-(3-(trifluoromethyl)benzamido-5-(5nitrothiophen-2-yl)methyleneaminothiophene- 3,4-dicarboxylate (C29) also possessed the best activity, whose IC₅₀ values were (0.47±0.03) and (0.41±0.04) μmol/L against HT-29 and HepG2, respectively, better than positive control drug doxorubicin (DOX) (IC₅₀ values were (1.15±0.03), (0.86±0.07) and (0.86±0.02) μmol/L against HT-29, A549, and HepG2, respectively).

Key words: diethyl 2,5-diaminothiophene-3,4-dicarboxylate, anticancer activity

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Weishu Zhang, Lifei Nie, Khurshed Bozorov, Haji Akber Aisa, Jiangyu Zhao. Synthesis of Diethyl 2,5-Diaminothiophene-3,4-dicarboxylate Derivatives and Antitumor Activity Study[J]. Chinese Journal of Organic Chemistry, 2023, 43(7): 2543-2552.

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Fig. & Tab. 5

References 19

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Compd.	R	IC₅₀^a/(μmol/L)
Compd.	R	HeLa	HT-29	A549	HepG2	L02
C1	C₆H₅	19.04±1.00	1.11±0.24	1.44±0.20	5.85±0.21	—
C2	Thien-2-yl	—	—	10.94±0.39	8.83±0.44	—
C3	Naphthyl-2	7.30±1.27	—	3.96±1.05	8.97±0.41	—
C4	CH₂C₆H₅	6.36±1.63	0.63±0.03	5.08±0.60	1.27±0.07	—
C5	C₂H₄C₆H₅	1.46±0.44	0.86±0.01	2.04±0.37	—	—
C6	C(CH₂)C₆H₅	26.67±2.92	2.72±1.65	9.58±3.12	36.51±2.18	—
C7	Pyran-4-yl	—	—	14.11±0.42	6.5±0.32	—
C8	(CH₂)₆	0.40±0.06	—	1.14±0.07	6.80±0.36	9.17±0.89
C9	(CH₂)₅	1.77±0.01	1.15±0.21	1.94±0.60	2.70±0.19	—
C10	(CH₂)₄	—	—	—	—	—
C11	(CH₂)₃	—	—	—	—	—
C12	C₃H₇	—	15.84±0.57	—	27.03±0.97	—
C13	C₄H₉	1.89±0.51	1.11±0.16	2.67±1.32	0.38±0.03	—
C14	C₆H₁₃	8.29±0.42	0.83±0.03	6.69±0.21	—	35.48±3.11
C15	C₇H₁₅	—	—	—	—	—
C16	4-CH₃C₆H₄	—	9.53±0.48	23.28±1.03	11.42±0.51	—
C17	4-CH₃OC₆H₄	—	—	—	1.47±0.08	—
C18	4-FC₆H₄	26.21±0.95	—	3.34±0.09	—	—
C19	4-ClC₆H₄	28.73±1.38	2.92±0.22	8.52±0.24	3.48±0.19	—
C20	3-ClC₆H₄	—	—	—	—	—
C21	2-ClC₆H₄	—	—	—	—	—
C22	4-BrC₆H₄	0.83±0.04	2.78±0.06	—	7.52±0.66	—
C23	3-BrC₆H₄	—	32.26±1.64	30.01±1.51	—	—
C24	2-BrC₆H₄	2.49±0.13	27.67±1.11	15.68±0.51	—	—
C25	4-CF₃OC₆H₄	—	0.35±0.07	0.66±0.09	0.96±0.06	2.68±0.21
C26	3-CF₃OC₆H₄	8.11±0.49	—	—	10.9±0.51	—
C27	2-CF₃OC₆H₄	—	—	—	—	—
C28	4-CF₃C₆H₄	9.62±2.93	1.59±0.07	7.54±1.74	10.09±0.78	—
C29	3-CF₃C₆H₄	6.80±0.25	0.47±0.03	2.03±0.09	0.41±0.04	—
C30	2-CF₃C₆H₄	0.92±0.02	—	2.51±0.07	9.03±0.38	—
DOX		0.55±0.05	1.15±0.03	0.86±0.07	0.86±0.02	—

Compd.	R	IC₅₀^a/(μmol/L)
Compd.	R	HeLa	HT-29	A549	HepG2	L02
C1	C₆H₅	19.04±1.00	1.11±0.24	1.44±0.20	5.85±0.21	—
C2	Thien-2-yl	—	—	10.94±0.39	8.83±0.44	—
C3	Naphthyl-2	7.30±1.27	—	3.96±1.05	8.97±0.41	—
C4	CH₂C₆H₅	6.36±1.63	0.63±0.03	5.08±0.60	1.27±0.07	—
C5	C₂H₄C₆H₅	1.46±0.44	0.86±0.01	2.04±0.37	—	—
C6	C(CH₂)C₆H₅	26.67±2.92	2.72±1.65	9.58±3.12	36.51±2.18	—
C7	Pyran-4-yl	—	—	14.11±0.42	6.5±0.32	—
C8	(CH₂)₆	0.40±0.06	—	1.14±0.07	6.80±0.36	9.17±0.89
C9	(CH₂)₅	1.77±0.01	1.15±0.21	1.94±0.60	2.70±0.19	—
C10	(CH₂)₄	—	—	—	—	—
C11	(CH₂)₃	—	—	—	—	—
C12	C₃H₇	—	15.84±0.57	—	27.03±0.97	—
C13	C₄H₉	1.89±0.51	1.11±0.16	2.67±1.32	0.38±0.03	—
C14	C₆H₁₃	8.29±0.42	0.83±0.03	6.69±0.21	—	35.48±3.11
C15	C₇H₁₅	—	—	—	—	—
C16	4-CH₃C₆H₄	—	9.53±0.48	23.28±1.03	11.42±0.51	—
C17	4-CH₃OC₆H₄	—	—	—	1.47±0.08	—
C18	4-FC₆H₄	26.21±0.95	—	3.34±0.09	—	—
C19	4-ClC₆H₄	28.73±1.38	2.92±0.22	8.52±0.24	3.48±0.19	—
C20	3-ClC₆H₄	—	—	—	—	—
C21	2-ClC₆H₄	—	—	—	—	—
C22	4-BrC₆H₄	0.83±0.04	2.78±0.06	—	7.52±0.66	—
C23	3-BrC₆H₄	—	32.26±1.64	30.01±1.51	—	—
C24	2-BrC₆H₄	2.49±0.13	27.67±1.11	15.68±0.51	—	—
C25	4-CF₃OC₆H₄	—	0.35±0.07	0.66±0.09	0.96±0.06	2.68±0.21
C26	3-CF₃OC₆H₄	8.11±0.49	—	—	10.9±0.51	—
C27	2-CF₃OC₆H₄	—	—	—	—	—
C28	4-CF₃C₆H₄	9.62±2.93	1.59±0.07	7.54±1.74	10.09±0.78	—
C29	3-CF₃C₆H₄	6.80±0.25	0.47±0.03	2.03±0.09	0.41±0.04	—
C30	2-CF₃C₆H₄	0.92±0.02	—	2.51±0.07	9.03±0.38	—
DOX		0.55±0.05	1.15±0.03	0.86±0.07	0.86±0.02	—

2,5-二氨基噻吩-3,4-二羧酸二乙酯衍生物的合成及抗肿瘤活性研究

Synthesis of Diethyl 2,5-Diaminothiophene-3,4-dicarboxylate Derivatives and Antitumor Activity Study

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