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

doi:10.6023/cjoc202210040

摘要/Abstract

以含硫杂环噻吩为母核, 设计并合成了30个2,5-二氨基噻吩-3,4-二羧酸二乙酯衍生物, 经¹H NMR、¹³C NMR和HRMS进行了结构确证. 用噻唑蓝(MTT)法测定该系列化合物对HeLa(人宫颈癌)、HT-29(人结肠癌)、A549(人非小细胞肺癌)、HepG2(人肝癌)四种肿瘤细胞的体外抗增殖活性. 结果表明, 部分化合物表现出良好的抗增殖活性, 其中2-(4-(三氟甲氧基)苯甲酰胺基-5-(5-硝基噻吩-2-基)亚甲基氨基噻吩-3,4-二羧酸二乙酯(C25)对HT-29、A549两种肿瘤细胞均表现出明显的抗增殖活性, IC₅₀值分别为(0.35±0.07)和(0.66±0.09) μmol/L; 2-(3-(三氟甲基)苯甲酰胺基)-5-(5-硝基噻吩-2-基)亚甲基氨基噻吩-3,4-二羧酸二乙酯(C29)对HT-29、HepG2两种肿瘤细胞也表现出明显的抗增殖活性, IC₅₀值分别为(0.47±0.03)和(0.41±0.04) μmol/L, 其抑制活性均优于阳性对照药阿霉素(DOX)[对HT-29、A549、HepG2的IC₅₀值分别为(1.15±0.03)、(0.86±0.07)、(0.86±0.02) μmol/L].

关键词: 2,5-二氨基噻吩-3,4-二羧酸二乙酯, 抗肿瘤活性

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

引用此文

张维舒, 聂礼飞, Khurshed Bozorov, 阿吉艾克拜尔•艾萨, 赵江瑜. 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[J]. 有机化学, 2023, 43(7): 2543-2552.

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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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	—