Acta Pharmacologica Sinica 2006 September; 27 (9): 1259-1272; doi: 10.1111/j.1745-7254.2006.00437.x

Acta Pharmacologica Sinica 2006 September; 27 (9): 1259-1272; doi: 10.1111/j.1745-7254.2006.00437.x

Original Article

Design, synthesis and antitumor evaluation of a new series of N-substituted-thiourea derivatives

Jian LI², Jin-zhi TAN², Li-li CHEN², Jian ZHANG², Xu SHEN^2,3, Chang-lin MEI^4,6, Li-li FU⁴, Li-ping LIN⁵, Jian DING⁵, Bing XIONG², Xi-shan XIONG⁴, Hong LIU^2,6, Xiao-min LUO^2,6, Hua-liang JIANG^2,3

²Drug Discovery and Design Centre, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, China; ³School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China; ⁴Division of Nephrology, Department of Internal Medicine, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China; ⁵Division of Antitumor Pharmacology, Shanghai Institute of Materia Medica, Shanghai 201203, China

Aim: To design and synthesize a novel class of protein tyrosine kinase inhibitors, featuring the N-(2-oxo-1,2-dihydroquinolin-3-yl-methyl)-thiourea framework.

Methods: First, compounds 1 and 2 were identified using the virtual screening approach in conjunction with binding assay based on surface plasmon resonance. Subsequently, 3 regions of compounds 1 and 2 were selected for chemical modifica-tion. All compounds were characterized potent inhibitory activities toward the human lung adenocarcinoma cell line SPAC1.

Results: Forty new compounds (1-2, 3a-g, 4a-w, and 5a-l) were designed, synthesized and bioassayed. Six compounds (1, 3e, 4l, 4w, 5a, and 5b) were found to show promising inhibitory activity against the SPAC1 tumor cell line. The inhibitory activity of compound 5a increases approximately 10 times more than that of the original compound 1.

Conclusion: This study provides a promising new template with potential antitumor activity.

Keywords: N-substituted-thiourea derivatives; anti-tumor; SPAC1; tyrosine kinase inhibitor; virtual screening

¹Project supported by the State Key Program of Basic Research of China (No 2002CB512802), the 863 Hi-Tech Program (No 2002AA233061, 2002AA104270) and the National Natural Science Foundation of China (No 20372069, 29725203, and 20472094).

⁶Correspondence to Dr Hong LIU, Dr Xiao-min LUO, Dr Chang-lin MEI.
Phn 86-21-5080-6600, ext 5416.
Fax 86-21-5080-7088.
E-mail hliu@mail.shcnc.ac.cn ; xmluo@mail.shcnc.ac.cn ; chlmei@public1.sta.net.cn
Received 2006-03-17 Accepted 2006-06-06

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