Synthesis and structure-activity relationship of 6-arylureido-3-pyrrol-2-ylmethylideneindolin-2-one derivatives as potent receptor tyrosine kinase inhibitors
Resource
BIOORGANIC & MEDICINAL CHEMISTRY, 18(13), 4674-4686
Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Journal Volume
18
Journal Issue
13
Pages
4674-4686
Date Issued
2010
Date
2010
Author(s)
Khanwelkar, Rahul R.
Chen, Grace Shiahuy
Wang, Hsiao-Chun
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
Liu, Chih-Peng
Tu, Chia-Mu
Hu, Tsan-Lin
Tsai, Yuan-Jang
Chern, Ji-Wang
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. ? 2010 Elsevier Ltd. All rights reserved.
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Other Subjects
1 (3,4 dimethoxyphenyl) 3 [2 oxo 3 (1h pyrrol 2 ylmethylene) 2,3 dihydro 1h indol 6 yl] urea; 1 (4 chlorophenyl) 3 [2 oxo 3 (1h pyrrol 2 ylmethylene) 2,3 dihydro 1h indol 6 yl] urea; 1 (4 methoxyphenyl) 3 [2 oxo 3 (1h pyrrol 2 ylmethylene) 2,3 dihydro 1h indol 6 yl] urea; 1 [2 oxo 3 (1h pyrrol 2 ylmethylene) 2,3 dihydro 1h indol 6 yl] 3 (4 phenoxyphenyl) urea; 1 [2 oxo 3 (1h pyrrol 2 ylmethylene) 2,3 dihydro 1h indol 6 yl] 3 (4 tolyl) urea; 1 [2 oxo 3 (1h pyrrol 2 ylmethylene) 2,3 dihydro 1h indol 6 yl] 3 phenyl urea; 1 [3 (3,5 dimethyl 4 phenyl 1h pyrrol 2 ylmethylene) 2 oxo 2,3 dihydro 1h indol 6 yl] 3 (4 methoxyphenyl) urea; 1 biphenyl 4 yl 3 [2 oxo 3 (1h pyrrol 2 ylmethylene) 2,3 dihydro 1h indol 6 yl] urea; 1 naphthalen 2 yl 3 [2 oxo 3 (1h pyrrol 2 ylmethylene) 2,3 dihydro 1h indol 6 yl] urea; 2,4 dimethyl 5 [2 oxo 6 (3 4 tolylureido) 1,2 dihydroindol 3 ylidene methyl] 1h pyrrole 3 carboxylic acid; 2,4 dimethyl 5 [2 oxo 6 (3 phenylureido) 1,2 dihydroindol 3 ylidene methyl] 1h pyrrole 3 carboxylic acid; 3 [5 (6 (3 (4 methoxyphenyl) ureido) 2 oxo 1,2 dihydroindol 3 ylidene methyl) 2,4 dimethyl 1h pyrrol 3 yl] propionic acid; 4 methyl 5 [2 oxo 6 (3 phenylureido) 1,2 dihydroindol 3 ylidenemethyl] 1h pyrrole 2 carboxylic acid; 5 [6 (3 (4 chlorophenyl) ureido) 2 oxo 1,2 dihydroindol 3 ylidene methyl] 2,4 dimethyl 1h pyrrole 3 carboxylic acid; 5 [6 (3 (4 chlorophenyl) ureido) 2 oxo 1,2 dihydroindol 3 ylidene methyl] 4 methyl 1h pyrrole 2 carboxylic acid; 5 [6 (3 (4 methoxyphenyl) ureido) 2 oxo 1,2 dihydroindol 3 ylidene methyl] 1h pyrrole 2 carboxylic acid; 5 [6 (3 (4 methoxyphenyl) ureido) 2 oxo 1,2 dihydroindol 3 ylidene methyl] 2,4 dimethyl 1h pyrrole 3 carboxylic acid; 5 [6 (3 (4 methoxyphenyl) ureido) 2 oxo 1,2 dihydroindol 3 ylidene methyl] 4 methyl 1h pyrrole 3 carboxylic acid; 5 [6 (3 (4 methoxyphenyl) urido) 2 oxo 1,2 dihydro indol 3 ylidene methyl] thiophen 2 carboxylic acid; 6 arylureido 3 pyrrol 2 ylmethylideneindolin 2 one derivative; [2,4 dimethyl 5 (2 oxo 6 (3 phenylureido) 1,2 dihydroindol 3 ylidene methyl) 1h pyrrol 3 yl] acetic acid; [5 (6 (3 (4 methoxyphenyl) ureido) 2 oxo 1,2 dihydroindol 3 ylidene methyl) 2,4 dimethyl 1h pyrrol 3 yl] acetic acid; aurora A kinase; oxindole; platelet derived growth factor receptor; protein tyrosine kinase inhibitor; unclassified drug; ureidoindolin 2 one derivative; vasculotropin receptor; animal experiment; animal model; antineoplastic activity; area under the curve; article; cancer inhibition; cell function; controlled study; cytotoxicity; drug clearance; drug distribution; drug half life; drug identification; drug screening; drug synthesis; enzyme inhibition; female; leukemia cell; male; maximum plasma concentration; mouse; nonhuman; rat; structure activity relation; time to maximum plasma concentration; tumor xenograft; Western blotting; Animals; Binding Sites; Cell Line, Tumor; Computer Simulation; Drug Screening Assays, Antitumor; Humans; Indoles; Leukemia, Myeloid; Mice; Protein Kinase Inhibitors; Protein-Serine-Threonine Kinases; Pyrroles; Receptor, Epidermal Growth Factor; Receptors, Platelet-Derived Growth Factor; Structure-Activity Relationship; Transplantation, Heterologous; Urea; Mus musculus
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