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Synthesis and structure–activity relationship of 6-arylureido-3-pyrrol-2-ylmethylideneindolin-2-one derivatives as potent receptor tyrosine kinase inhibitors

Authors :
Khanwelkar, Rahul R.
Chen, Grace Shiahuy
Wang, Hsiao-Chun
Yu, Chao-Wu
Huang, Chiung-Hua
Lee, On
Chen, Chih-Hung
Hwang, Chrong-Shiong
Ko, Ching-Huai
Chou, Nien-Tzu
Lin, Mai-Wei
Wang, Ling-mei
Chen, Yen-Chun
Hseu, Tzong-Hsiung
Chang, Chia-Ni
Hsu, Hui-Chun
Lin, Hui-Chi
Shih, Ying-Chu
Chou, Shuen-Hsiang
Tseng, Hsiang-Wen
Source :
Bioorganic & Medicinal Chemistry. Jul2010, Vol. 18 Issue 13, p4674-4686. 13p.
Publication Year :
2010

Abstract

Abstract: A series of new ureidoindolin-2-one derivatives were synthesized and evaluated as inhibitors of receptor tyrosine kinases. Investigation of structure–activity relationships at positions 5, 6, and 7 of the oxindole skeleton led to the identification of 6-ureido-substituted 3-pyrrolemethylidene-2-oxindole derivatives that potently inhibited both the vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) families of receptor tyrosine kinases. Several derivatives showed potency against the PDGFR inhibiting both its enzymatic and cellular functions in the single-digit nanomolar range. Among them, compound 35 was a potent inhibitor against tyrosine kinases, including VEGFR and PDGFR families, as well as Aurora kinases. Inhibitor 36 (non-substituted on the pyrrole or phenyl ring) had a moderate pharmacokinetic profile and completely inhibited tumor growth initiated with the myeloid leukemia cell line, MV4-11, in a subcutaneous xenograft model in BALB/c nude mice. [Copyright &y& Elsevier]

Details

Language :
English
ISSN :
09680896
Volume :
18
Issue :
13
Database :
Academic Search Index
Journal :
Bioorganic & Medicinal Chemistry
Publication Type :
Academic Journal
Accession number :
51435523
Full Text :
https://doi.org/10.1016/j.bmc.2010.05.021