新型齐多夫定与4-苯胺喹唑啉骨架拼接产物的合成及体外抗肿瘤活性

doi:10.6023/cjoc202205016

摘要/Abstract

为寻找新型的抗肿瘤药物, 合成了一系列齐多夫定与N-苯基喹唑啉-4-胺骨架的拼接产物. 通过噻唑蓝(MTT)法评价它们对人肺癌细胞(A549)、人肺癌耐药细胞(A549/DDP)、人肝癌细胞(HepG2)、人宫颈癌细胞(Hela)、人乳腺癌细胞(MCF-7)的抑制活性. 采用酶联免疫法评价合成衍生物对表皮生长因子受体(EGFR)的抑制作用. 结果显示大多数目标产物对5种细胞具有显著的抗肿瘤活性. 特别是1-((2R,5S)-5-羟甲基-4-(4-(((4-((2-氯-4-碘苯基)氨基)-6-甲氧基喹唑啉-7-基)氧基)甲基)-1H-1,2,3-三氮唑-1-基)四氢呋喃-2-基)-5-甲基嘧啶-2,4(1H,3H)-二酮(8b), 对HepG2细胞株具有最好的抗肿瘤活性, 其IC₅₀值为(0.79±0.18) μmol/L, 抗肿瘤活性明显优于阳性对照厄洛替尼和齐多夫定. 1-((2R,5S)-5-羟甲基-4-(4-(((4-((3-氯-4-氟苯基)氨基)-6-甲氧基喹唑啉-7-基)氧基)甲基)-1H-1,2,3-三氮唑-1-基)四氢呋喃-2-基)-5-甲基嘧啶- 2,4(1H,3H)-二酮(8a)和1-((2R,5S)-5-羟甲基-4-(4-(((4-((3,4,5-三氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)甲基)-1H-1,2,3-三氮唑-1-基)四氢呋喃-2-基)-5-甲基嘧啶-2,4(1H,3H)-二酮(8l)对A549、Hela、A549/DDP肿瘤细胞都表现出良好的活性, 且IC₅₀值小于5 μmol/L. 分子对接结果表明化合物8a和8l与EGFR的多个氨基酸残基具有良好的结合作用.

关键词: 喹唑啉, 齐多夫定, 衍生物, 抗肿瘤, 表皮生长因子受体(EGFR)抑制剂

Seventeen novel compounds of Zidovudine and 4-anilinoquinazoline were synthesized for use as anti-tumor reagents. The target compounds are subjected to antitumor screening against human cancer cells, namely, A549 (lung carcinoma), A549/DDP (lung carcinoma/Cisplatin-resistant), HepG2 (liver carcinoma), Hela (cervical carcinoma), and MCF-7 (breast carcinoma), using methyl thiazolyl tetrazolium (MTT) assay. In addition, their inhibition of epidermal growth factor receptor (EGFR) was assessed by enzyme linked immunosorbent assay (ELISA). Anticancer bioassays indicated that most of the compounds exhibited appreciable anticancer activity against five human cancer cell lines. In particular, 1-(4-(5-(((4-((2-chloro- 4-iodophenyl)amino)-6-methoxyquinazolin-7-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)-5-(hydroxymethyl)tetrahydrofuran-2-yl)- 5-methylpyrimidine-2,4(1H,3H)-dione (8b) was found to be the most potent anticancer agent with an IC₅₀ value of (0.79±0.18) μmol/L against HepG2, respectively. Among the compounds tested, 1-(4-(5-(((4-((3-chloro-4-fluorophenyl)amino)-6- methoxyquinazolin-7-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)-5-(hydroxymethyl)tetrahydrofuran-2-yl)-5-methylpyrimidine-2,4 (1H,3H)-dione (8a) and 1-(5-(hydroxymethyl)-4-(4-(((7-methoxy-4-((3,4,5-trifluorophenyl)amino)quinazolin-6-yl)oxy)me- thyl)-1H-1,2,3-triazol-1-yl)tetrahydrofuran-2-yl)-5-methylpyrimidine-2,4(1H,3H)-dione (8l) showed significant inhibition against the five human cancer cell lines. Molecular docking results also showed that compounds 8a and 8l bound well to the EGFR binding sites.

Key words: quinazoline, zidovudine, derivatives, antitumor, epidermal growth factor receptor (EGFR) inhibitors

引用此文

梁光平, 王维, 朱绪秀, 梁光焰, 杨俊, 王道平. 新型齐多夫定与4-苯胺喹唑啉骨架拼接产物的合成及体外抗肿瘤活性[J]. 有机化学, 2022, 42(9): 2793-2805.

Guangping Liang, Wei Wang, Xuxiu Zhu, Guangyan Liang, Jun Yang, Daoping Wang. Synthesis and in Vitro Anti-tumor Activity of Novel Spliced Compounds of Zidovudine and 4-Anilinoquinazolines[J]. Chinese Journal of Organic Chemistry, 2022, 42(9): 2793-2805.

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参考文献 18

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Compd.	(IC₅₀±SD)/(μmol•L^–1)
Compd.	HepG2	A549	Hela	MCF-7	A549/DDP
8a	1.25±0.28	2.13±0.31	1.79±0.23	6.13±0.66	4.94±1.09
8b	0.79±0.18	18.51±0.99	7.27±0.42	>40	28.83±1.27
8c	29.14±1.16	8.89±0.39	5.53±0.75	5.08±0.59	11.48±0.92
8d	10.85±0.55	19.07±1.41	21.89±1.33	>40	37.49±1.20
8e	5.54±0.25	26.75±1.05	7.22±0.85	5.12±0.78	33.16±1.43
8f	35.22±0.82	5.22±0.44	2.38±0.17	1.29±0.21	8.91±0.36
8g	37.93±0.88	>40	17.03±0.86	22.96±0.71	>40
8h	>40	>40	>40	23.43±1.11	>40
8i	3.17±0.74	>40	21.78±0.47	16.33±0.22	>40
8j	5.40±0.92	>40	17.47±0.86	2.78±0.39	>40
8k	2.51±0.82	7.27±0.95	12.40±1.04	1.18±0.13	11.63±0.64
8l	7.09±0.46	2.37±0.61	1.04±0.33	1.32±0.26	3.02±0.42
8m	20.04±1.01	>40	>40	21.89±0.83	>40
8n	>40	>40	>40	27.16±1.07	>40
8o	28.87±1.12	6.95±0.72	3.04±0.51	3.12±0.35	8.88±0.89
8p	>40	38.50±1.39	19.15±0.99	12.21±0.69	34.39±1.22
8q	>40	>40	>40	>40	>40
8r	1.23±0.15	>40	31.44±1.32	8.57±0.65	>40
Erlotinib	8.91±0.83	1.39±0.49	0.42±0.22	0.091±0.28	2.37±0.39
AZT	6.07±0.53	9.33±0.93	>40	36.87±1.18	14.51±0.77

Compd.	(IC₅₀±SD)/(μmol•L^–1)
Compd.	HepG2	A549	Hela	MCF-7	A549/DDP
8a	1.25±0.28	2.13±0.31	1.79±0.23	6.13±0.66	4.94±1.09
8b	0.79±0.18	18.51±0.99	7.27±0.42	>40	28.83±1.27
8c	29.14±1.16	8.89±0.39	5.53±0.75	5.08±0.59	11.48±0.92
8d	10.85±0.55	19.07±1.41	21.89±1.33	>40	37.49±1.20
8e	5.54±0.25	26.75±1.05	7.22±0.85	5.12±0.78	33.16±1.43
8f	35.22±0.82	5.22±0.44	2.38±0.17	1.29±0.21	8.91±0.36
8g	37.93±0.88	>40	17.03±0.86	22.96±0.71	>40
8h	>40	>40	>40	23.43±1.11	>40
8i	3.17±0.74	>40	21.78±0.47	16.33±0.22	>40
8j	5.40±0.92	>40	17.47±0.86	2.78±0.39	>40
8k	2.51±0.82	7.27±0.95	12.40±1.04	1.18±0.13	11.63±0.64
8l	7.09±0.46	2.37±0.61	1.04±0.33	1.32±0.26	3.02±0.42
8m	20.04±1.01	>40	>40	21.89±0.83	>40
8n	>40	>40	>40	27.16±1.07	>40
8o	28.87±1.12	6.95±0.72	3.04±0.51	3.12±0.35	8.88±0.89
8p	>40	38.50±1.39	19.15±0.99	12.21±0.69	34.39±1.22
8q	>40	>40	>40	>40	>40
8r	1.23±0.15	>40	31.44±1.32	8.57±0.65	>40
Erlotinib	8.91±0.83	1.39±0.49	0.42±0.22	0.091±0.28	2.37±0.39
AZT	6.07±0.53	9.33±0.93	>40	36.87±1.18	14.51±0.77

Compd.	Inhibition rate/%
Compd.	0.01 μmol/L	0.1 μmol/L	1 μmol/L	10 μmol/L	100 μmol/L
8a	29.58	50.59	55.15	69.79	73.95
8b	24.99	34.88	49.90	54.66	59.82
8c	15.03	24.72	39.65	50.24	64.46
8d	15.18	24.99	39.35	50.09	59.93
8e	14.77	25.30	39.70	54.75	60.60
8f	19.79	34.91	44.98	50.03	59.80
8g	25.56	34.97	50.16	59.80	64.83
8h	20.03	35.52	45.42	50.04	55.50
8i	14.70	20.22	24.61	44.65	60.28
8j	20.25	29.72	39.76	50.27	60.07
8k	14.38	24.84	40.41	59.75	69.80
8l	40.31	49.67	54.58	65.42	80.55
8m	15.02	19.91	29.79	40.00	49.95
8n	10.22	20.28	24.54	40.27	54.23
8o	19.65	29.78	40.41	54.23	74.39
8p	9.98	20.10	30.25	50.22	64.25
8q	15.89	25.19	35.48	44.19	54.93
8r	9.67	19.71	39.76	44.60	55.29
Erlotinib	49.21	60.00	64.87	75.38	79.91
AZT	29.90	40.26	50.06	54.88	64.78

Compd.	Inhibition rate/%
Compd.	0.01 μmol/L	0.1 μmol/L	1 μmol/L	10 μmol/L	100 μmol/L
8a	29.58	50.59	55.15	69.79	73.95
8b	24.99	34.88	49.90	54.66	59.82
8c	15.03	24.72	39.65	50.24	64.46
8d	15.18	24.99	39.35	50.09	59.93
8e	14.77	25.30	39.70	54.75	60.60
8f	19.79	34.91	44.98	50.03	59.80
8g	25.56	34.97	50.16	59.80	64.83
8h	20.03	35.52	45.42	50.04	55.50
8i	14.70	20.22	24.61	44.65	60.28
8j	20.25	29.72	39.76	50.27	60.07
8k	14.38	24.84	40.41	59.75	69.80
8l	40.31	49.67	54.58	65.42	80.55
8m	15.02	19.91	29.79	40.00	49.95
8n	10.22	20.28	24.54	40.27	54.23
8o	19.65	29.78	40.41	54.23	74.39
8p	9.98	20.10	30.25	50.22	64.25
8q	15.89	25.19	35.48	44.19	54.93
8r	9.67	19.71	39.76	44.60	55.29
Erlotinib	49.21	60.00	64.87	75.38	79.91
AZT	29.90	40.26	50.06	54.88	64.78

Compd.	结合能/ (kJ•mol^–1)	氢键				疏水作用
Compd.	结合能/ (kJ•mol^–1)	数量	键长/nm	残基	数量	残基
8a	–35.6	2	0.310 0.314	Asn469 Asn469	12	Arg470, Ser468, Gly471, Ile467, Cys446, Thr450, Val481, Cys482, Glu472, Asn449, Ile466, Arg470
8l	–33.9	3	0.297 0.300 0.318	Lys407 Gly410 Gln408	11	Thr406, Gln8, Gly9, Thr10, Ser11, Met87, Lys322, Ser324, Leu325, His346, His409
AZT	–25.5	6	0.312 0.281 0.316 0.309 0.327 0.293	Pro272 Arg300 Ser433 Arg403 Asn274 Arg273	3	Tyr275, Val299, Arg405
Erlotinib	–25.1	2	0.308 0.309	Arg141 Gln139	8	Ile189, Ser137, Met154, Ile138, Glu136, Phe156, Trp140, Met152