TY - JOUR
T1 - Design and synthesis of diarylamines and diarylethers as cytotoxic antitumor agents
AU - Wang, Xiao Feng
AU - Tian, Xing Tao
AU - Ohkoshi, Emika
AU - Qin, Bingjie
AU - Liu, Yi Nan
AU - Wu, Pei Chi
AU - Hour, Mann Jen
AU - Hung, Hsin Yi
AU - Qian, Keduo
AU - Huang, Rong
AU - Bastow, Kenneth F.
AU - Janzen, William P.
AU - Jin, Jian
AU - Morris-Natschke, Susan L.
AU - Lee, Kuo Hsiung
AU - Xie, Lan
N1 - Funding Information:
This investigation was supported by Grants 81120108022 and 30930106 from the Natural Science Fundation of China (NSFC), and 2006DFA33560 from the Ministry of Science and Technology Commission in China awarded to Lan Xie and NIH Grant CA17625-32 from the National Cancer Institute awarded to K.H. Lee. This study was also supported in part by the Taiwan Department of Health, China Medical University Hospital Cancer Research Center of Excellence (DOH100-TD-C-111-005).
PY - 2012/10/1
Y1 - 2012/10/1
N2 - Based on a shared structural core of diarylamine in several known anticancer drugs as well as a new cytotoxic hit 6-chloro-2-(4-cyanophenyl)amino- 3-nitropyridine (7), 30 diarylamines and diarylethers were designed, synthesized, and evaluated for cytotoxic activity against A549, KB, KB-vin, and DU145 human tumor cell lines (HTCL). Four new leads 11e, 12, 13a, and 13b were discovered with GI50 values ranging from 0.33 to 3.45 μM. Preliminary SAR results revealed that a diarylamine or diarylether could serve as an active structural core, meta-chloro and ortho-nitro groups on the A-ring (either pyridine or phenyl ring) were necessary and crucial for cytotoxic activity, and the para-substituents on the other phenyl ring (B-ring) were related to inhibitory selectivity for different tumor cells. In an investigation of potential biological targets of the new leads, high thoughput kinase screening discovered that new leads 11e, 12 and 13b especially inhibit Mer tyrosine kinase, a proto-oncogene associated with munerous tumor types, with IC50 values of 2.2-3.0 μM. Therefore, these findings provide a good starting point to optimize a new class of compounds as potential anticancer agents, particularly targeting Mer tyrosine kinase.
AB - Based on a shared structural core of diarylamine in several known anticancer drugs as well as a new cytotoxic hit 6-chloro-2-(4-cyanophenyl)amino- 3-nitropyridine (7), 30 diarylamines and diarylethers were designed, synthesized, and evaluated for cytotoxic activity against A549, KB, KB-vin, and DU145 human tumor cell lines (HTCL). Four new leads 11e, 12, 13a, and 13b were discovered with GI50 values ranging from 0.33 to 3.45 μM. Preliminary SAR results revealed that a diarylamine or diarylether could serve as an active structural core, meta-chloro and ortho-nitro groups on the A-ring (either pyridine or phenyl ring) were necessary and crucial for cytotoxic activity, and the para-substituents on the other phenyl ring (B-ring) were related to inhibitory selectivity for different tumor cells. In an investigation of potential biological targets of the new leads, high thoughput kinase screening discovered that new leads 11e, 12 and 13b especially inhibit Mer tyrosine kinase, a proto-oncogene associated with munerous tumor types, with IC50 values of 2.2-3.0 μM. Therefore, these findings provide a good starting point to optimize a new class of compounds as potential anticancer agents, particularly targeting Mer tyrosine kinase.
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U2 - 10.1016/j.bmcl.2012.08.014
DO - 10.1016/j.bmcl.2012.08.014
M3 - Article
C2 - 22932313
AN - SCOPUS:84866347315
VL - 22
SP - 6224
EP - 6228
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
SN - 0960-894X
IS - 19
ER -