Synthesis and in Vitro Anti-tumor Activity of Novel Spliced Compounds of Zidovudine and 4-Anilinoquinazolines

doi:10.6023/cjoc202205016

Abstract

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

Cite this article

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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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

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