Synthesis and In vitro Anticancer Activity of Novel Quinazoline Derivatives Containing Thiosemicarbazone Structure†

doi:10.7503/cjcu20130837

Abstract

Abstract:

To find new EGFR inhibitors, 15 novel quinazoline derivatives containing thiosemicarbazone structure were designed and synthesized from 2-amino-4,5-dimethoxybenzoic acid and formamidine acetate by the cyclization, chlorination, amination and condensation reactions. All structures of target compounds were confirmed by ¹H NMR,¹³C NMR, HRMS and elemental analysis. The in vitro anticancer activities of compounds 6a—6o against EGFR over-expressing of MCF-7(Human breast cancer), A549(Human pulmonary adenocarcinoma) and PC3(Human prostate cancer) cell lines were tested using colorimetric MTT assay. The results indicated that several compounds showed potent activity. Compounds 6a and 6o were more potent than Lapatinib, but slightly weaker than ADM against the three cell lines. The IC₅₀ values of compounds 6a and 6o against MCF-7 cell line were 6.97 and 6.99 μmol/L, against A549 were 5.15 and 3.11 μmol/L and against PC3 were 2.30 and 1.42 μmol/L, respectively. Preliminary structure-activity relationship was also discussed.

Key words: Epidermal growth factor receptor(EGFR), Quinazoline, Thiosemicarbazone, Anticancer activity

CLC Number:

O626.41

TrendMD:

LIU Haibin, LÜ Ping, PAN Ningning, AI Limei, LIU Yongxiang. Synthesis and In vitro Anticancer Activity of Novel Quinazoline Derivatives Containing Thiosemicarbazone Structure^†[J]. Chem. J. Chinese Universities, 2014, 35(5): 981.

Figures/Tables 4

References 22

[1]	He J. B., Wang X. G., Zhao X. Q., Liang Y. J., He H. W., Fu L. W., Eur. J. Med. Chem., 2012, 54, 925—930
[2]	Wu X. Q., Li M. D., Tang W. H., Zheng Y. G., Lian J. Q., Xu L., Ji M., Chem. Biol. Drug Des., 2011, 78(6), 932—940
[3]	Shallal H. M., Russu W. A., Eur. J. Med. Chem., 2011, 46(6), 2043—2057
[4]	Yang S., Li Z., Jin L.H., Song B. A., Liu G., Chen J., Chen Z., Hu D. Y., Xue W., Xu R. Q., Bioorg. Med. Chem. Lett., 2007, 17, 2193—2196
[5]	Liu F., Huang Y., Pestic. Biochem. Physiol., 2011, 101, 248—255
[6]	Ryu C. K., Kim Y. H., Im H. A., Kim J. Y., Yoon J. H., Kim A., Bioorg. Med. Chem. Lett., 2012, 22, 500—503
[7]	Mani C. P., Yakaiah T., Raghu R. R. A., Narsaiah B., Chakra R. N., Sridhar V., Venkateshwara R. J., Eur. J. Med. Chem., 2008, 43, 846—852
[8]	Deng X. Q., Xiao C. R., Wei C. X., Quan Z. S., Chin. J. Org. Chem., 2011, 31(12), 2082—2087
	(邓先清, 肖春瑞, 魏成喜, 全哲山.有机化学, 2011,31(12), 2082—2087)
[9]	Tang J. H., Shi D. X., Wang X. Z., Liu X., Li J. R., Chem. J. Chinese Universities, 2012, 33(3), 501—506
	(唐健红, 史大昕, 王秀珍, 刘璇, 李加荣.高等学校化学学报, 2012,33(3), 501—506)
[10]	Chilin A., Conconi M. T., Marzaro G., Guiotto A., Urbani L., Tonus F., Parnigotto P., J. Med. Chem., 2010, 53(4), 1862—1866
[11]	Amin K. M., Georgey H. H., Awadallah F. M., Med. Chem. Res., 2011, 20, 1042—1053
[12]	Ren X. L., Wang X., Li Z. Y., You Q. D., Chin. J. New Drugs, 2005, 14(7), 821—826
	(任晓岚, 汪鑫, 李志裕, 尤启冬.中国新药杂志, 2005,14(7), 821—826)
[13]	Chilin A., Conconi M. T., Marzaro G., Guiotto A., Urbani L., Tonus F., Parnigotto P., J. Med. Chem., 2010, 53, 1862—1866
[14]	Wu X. Q., Li M. D., Tang W. H., Zheng Y. G., Lian J. Q., Xu L., Ji M., Chem. Biol. Drug Des., 2011, 78, 932—940
[15]	Li M. X., Zhang D., Zhang L. Z., Niu J. Y., Ji B. S., J. Organomet. Chem., 2011, 696, 852—858
[16]	Bharti N., Maury M. R., Naqvi F., Azam A., Bioorg. Med. Chem. Lett., 2000, 10(20), 2243—2245
[17]	Fujii N., Mallari J. P., Hansell E. J., Mackey Z., Doyle P., Zhou Y. M., Gut J., Rosenthal P. J., McKerrow J. H., Guy R. K., Bioorg. Med. Chem. Lett., 2005, 15(1), 121—123
[18]	Easmon J., Pürstinger G., Heinisch G., Roht T., Fiebig H. H., Holzer W., Jäger W., Jenny M., Hofmann J., J. Med. Chem., 2001, 44(13), 2164—2171
[19]	Chen J., Huang Y., Liu G., Afrasiabi Z., Sinn E., Padhye S., Ma Y., Toxicol. Appl. Pharm., 2004, 197, 40—48
[20]	Palanimuthu D., Samuelson A. G., Inorg. Chim. Acta, 2013, 408, 152—161
[21]	Zhon Z., Aotegen B., Xu H., Zhao S., Int. J. Biol. Macromol., 2012, 50, 1169—1174
[22]	Klayman D. L., Bartosevich J. F., Griffin T. S., Mason C. J., Scovill J. P., J. Med. Chem., 1979, 22(7), 855—862

Compound	R₁	R₂	Compound	R₁	R₂
6a	H	2-Pyridyl	6i	H	2-Nitrophenyl
6b	H	3-Pyridyl	6j	H	2-Fluorophenyl
6c	H	4-Pyridyl	6k	CH₃	4-Methoxyphenyl
6d	CH₃	3-Pyridyl	6l	Phenyl	Phenyl
6e	CH₃	4-Pyridyl	6m	CH₃	2-Furyl
6f	H	4-Fluorophenyl	6n	CH₃	2-Thienyl
6g	H	4-Methoxyphenyl	6o	CH₃	2-Thiazolyl
6h	H	4-Nitrophenyl

Compound	R₁	R₂	Compound	R₁	R₂
6a	H	2-Pyridyl	6i	H	2-Nitrophenyl
6b	H	3-Pyridyl	6j	H	2-Fluorophenyl
6c	H	4-Pyridyl	6k	CH₃	4-Methoxyphenyl
6d	CH₃	3-Pyridyl	6l	Phenyl	Phenyl
6e	CH₃	4-Pyridyl	6m	CH₃	2-Furyl
6f	H	4-Fluorophenyl	6n	CH₃	2-Thienyl
6g	H	4-Methoxyphenyl	6o	CH₃	2-Thiazolyl
6h	H	4-Nitrophenyl

Compound	R₁	R₂	IC₅₀/(μmol·L^-1)
Compound	R₁	R₂	MCF-7	A549	PC3
6a	H	2-Pyridyl	6.97±1.03	5.15±2.15	2.30±1.34
6b	H	3-Pyridyl	80.79±2.12	120.76±1.16	148.69±1.89
6c	H	4-Pyridyl	>150	>150	>150
6d	CH₃	3-Pyridyl	24.07±1.55	20.48±1.79	16.37±2.12
6e	CH₃	4-Pyridyl	>150	>150	>150
6f	H	4-Fluorophenyl	26.70±2.21	35.01±1.58	28.50±1.69
6g	H	4-Methoxyphenyl	>150	>150	>150
6h	H	4-Nitrophenyl	>150	>150	>150
6i	H	2-Nitrophenyl	60.97±1.36	4.74±1.18	>150
6j	H	2-Fluorophenyl	>150	5.30±2.02	>150
6k	CH₃	4-Methoxyphenyl	>150	>150	>150
6l	Phenyl	Phenyl	32.16±2.45	17.82±2.73	92.75±1.59
6m	CH₃	2-Furyl	>150	115.66±1.66	>150
6n	CH₃	2-Thienyl	29.49±2.42	28.68±1.67	24.93±1.93
6o	CH₃	2-Thiazolyl	6.99±1.77	3.11±2.58	1.42±1.82
ADM			0.97±2.63	0.86±1.52	0.74±1.85
Lapatinib			32.16±1.34	11.88±1.95	15.40±2.04

Compound	R₁	R₂	IC₅₀/(μmol·L^-1)
Compound	R₁	R₂	MCF-7	A549	PC3
6a	H	2-Pyridyl	6.97±1.03	5.15±2.15	2.30±1.34
6b	H	3-Pyridyl	80.79±2.12	120.76±1.16	148.69±1.89
6c	H	4-Pyridyl	>150	>150	>150
6d	CH₃	3-Pyridyl	24.07±1.55	20.48±1.79	16.37±2.12
6e	CH₃	4-Pyridyl	>150	>150	>150
6f	H	4-Fluorophenyl	26.70±2.21	35.01±1.58	28.50±1.69
6g	H	4-Methoxyphenyl	>150	>150	>150
6h	H	4-Nitrophenyl	>150	>150	>150
6i	H	2-Nitrophenyl	60.97±1.36	4.74±1.18	>150
6j	H	2-Fluorophenyl	>150	5.30±2.02	>150
6k	CH₃	4-Methoxyphenyl	>150	>150	>150
6l	Phenyl	Phenyl	32.16±2.45	17.82±2.73	92.75±1.59
6m	CH₃	2-Furyl	>150	115.66±1.66	>150
6n	CH₃	2-Thienyl	29.49±2.42	28.68±1.67	24.93±1.93
6o	CH₃	2-Thiazolyl	6.99±1.77	3.11±2.58	1.42±1.82
ADM			0.97±2.63	0.86±1.52	0.74±1.85
Lapatinib			32.16±1.34	11.88±1.95	15.40±2.04