Khanwelkar, Rahul R.Rahul R.KhanwelkarChen, Grace ShiahuyGrace ShiahuyChenWang, Hsiao-ChunHsiao-ChunWangYu, Chao-WuChao-WuYuHuang, Chiung-HuaChiung-HuaHuangLee, OnOnLeeChen, Chih-HungChih-HungChenHwang, Chrong-ShiongChrong-ShiongHwangKo, Ching-HuaiChing-HuaiKoChou, Nien-TzuNien-TzuChouLin, Mai-WeiMai-WeiLinWang, Ling-meiLing-meiWangChen, Yen-ChunYen-ChunChenHseu, Tzong-HsiungTzong-HsiungHseuChang, Chia-NiChia-NiChangHsu, Hui-ChunHui-ChunHsuLin, Hui-ChiHui-ChiLinShih, Ying-ChuYing-ChuShihChou, Shuen-HsiangShuen-HsiangChouTseng, Hsiang-WenHsiang-WenTsengLiu, Chih-PengChih-PengLiuTu, Chia-MuChia-MuTuHu, Tsan-LinTsan-LinHuTsai, Yuan-JangYuan-JangTsaiChern, Ji-WangJi-WangChern2012-10-192018-07-062012-10-192018-07-062010http://ntur.lib.ntu.edu.tw//handle/246246/243005A 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.en-US[SDGs]SDG31 (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 musculusjournal article10.1016/j.bmc.2010.05.021http://ntur.lib.ntu.edu.tw/bitstream/246246/243005/-1/111.pdf