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

Rahul R Khanwelkar; Grace Shiahuy Chen; Hsiao-Chun Wang; Chao-Wu Yu; Chiung-Hua Huang; On Lee; Chih-Hung Chen; Chrong-Shiong Hwang; Ching-Huai Ko; Nien-Tzu Chou; Mai-Wei Lin; Ling-Mei Wang; Yen-Chun Chen; Tzong-Hsiung Hseu; Chia-Ni Chang; Hui-Chun Hsu; Hui-Chi Lin; Ying-Chu Shih; Shuen-Hsiang Chou; Hsiang-Wen Tseng; Chih-Peng Liu; Chia-Mu Tu; Tsan-Lin Hu; Yuan-Jang Tsai; Ji-Wang Chern

doi:10.1016/j.bmc.2010.05.021

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

Bioorg Med Chem. 2010 Jul 1;18(13):4674-86. doi: 10.1016/j.bmc.2010.05.021. Epub 2010 May 12.

Affiliation

¹ School of Pharmacy, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.

PMID: 20570526
DOI: 10.1016/j.bmc.2010.05.021

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Aurora Kinases
Binding Sites
Cell Line, Tumor
Computer Simulation
Drug Screening Assays, Antitumor
ErbB Receptors / antagonists & inhibitors*
ErbB Receptors / metabolism
Humans
Indoles / chemistry*
Indoles / therapeutic use
Indoles / toxicity
Leukemia, Myeloid / drug therapy
Mice
Oxindoles
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / therapeutic use
Protein Kinase Inhibitors / toxicity
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / metabolism
Pyrroles / chemistry*
Pyrroles / therapeutic use
Pyrroles / toxicity
Receptors, Platelet-Derived Growth Factor / antagonists & inhibitors*
Receptors, Platelet-Derived Growth Factor / metabolism
Structure-Activity Relationship
Transplantation, Heterologous
Urea / analogs & derivatives*
Urea / chemistry
Urea / therapeutic use
Urea / toxicity

Substances

(Z)-1-(2-oxo-3-(1H-pyrrol-2-ylmethylene)-2,3-dihydro-1H-indol-6-yl)-3-phenyl-urea
(Z)-5-(6-(3-(4-methoxyphenyl)-ureido)-2-oxo-1,2-dihydroindol-3-ylidene-methyl)-4-methyl-1H-pyrrole-3-carboxylic acid
Indoles
Oxindoles
Protein Kinase Inhibitors
Pyrroles
indolin-2-one
2-oxindole
Urea
ErbB Receptors
Receptors, Platelet-Derived Growth Factor
Aurora Kinases
Protein Serine-Threonine Kinases