Synthesis and biological evaluations of 3-substituted indolin-2-ones: a novel class of tyrosine kinase inhibitors that exhibit selectivity toward particular receptor tyrosine kinases

Journal of Medicinal Chemistry
L SunC Tang

Abstract

3-Substituted indolin-2-ones have been designed and synthesized as a novel class of tyrosine kinase inhibitors which exhibit selectivity toward different receptor tyrosine kinases (RTKs). These compounds have been evaluated for their relative inhibitory properties against a panel of RTKs in intact cells. By modifying the 3-substituted indolin-2-ones, we have identified compounds which showed selective inhibition of the ligand-dependent autophosphorylation of various RTKs at submicromolar levels in cells. Structure-activity analysis for these compounds and their relative potency and selectivity to inhibit particular RTKs has determined that (1) 3-[(five-membered heteroaryl ring)methylidenyl]indolin-2-ones are highly specific against the VEGF (Flk-1) RTK activity, (2) 3-(substituted benzylidenyl)indolin-2-ones containing bulky group(s) in the phenyl ring at the C-3 position of indolin-2-ones showed high selectivity toward the EGF and Her-2 RTKs, and (3) the compound containing an extended side chain at the C-3 position of the indolin-2-one (16) exhibited high potency and selectivity when tested against the PDGF and VEGF (Flk-1) RTKs. Recent published crystallographic data for two of these 3-substituted indolin-2-ones provides a r...Continue Reading

Citations

Oct 19, 2001·Medicinal Research Reviews·P TraxlerJ Zimmermann
Sep 28, 2000·Biochemical and Biophysical Research Communications·A CaneM Crumeyrolle-Arias
Jan 27, 2004·Brain Research. Molecular Brain Research·Vardit RubovitchYosef Sarne
Apr 16, 2003·Analytical Biochemistry·Kolbrún Kristjánsdóttir, Johannes Rudolph
May 30, 2001·Journal of Pharmaceutical and Biomedical Analysis·Y ZhaoL Antonian
May 17, 2003·Bioorganic & Medicinal Chemistry Letters·Xiaoyuan LiCho Tang
Jul 11, 2003·Bioorganic & Medicinal Chemistry Letters·Jin-Jun LiuKin-Chun Luk
Aug 28, 2003·Bioorganic & Medicinal Chemistry Letters·Christopher AdamsBarry Wyman
May 9, 2000·Critical Reviews in Oncology/hematology·M Hagedorn, A Bikfalvi
Jan 5, 2002·Current Opinion in Pharmacology·R A Blake
Jul 5, 2008·Journal of Medicinal Chemistry·Aldo AndreaniMark W Kunkel
Nov 23, 2013·Journal of Natural Products·Koji UehataAtsushi Nishida
Jan 30, 2007·The Journal of Antibiotics·Yukihiro AsamiHiroyuki Osada
May 31, 2007·Chemical Communications : Chem Comm·Masahiro UenoYoshinori Kondo
Apr 10, 2010·Chemical Communications : Chem Comm·Satoshi UedaHideko Nagasawa
Jan 1, 2009·Acta Crystallographica. Section E, Structure Reports Online·Gang ChenJingfang Xu
Nov 14, 2000·Molecular and Cellular Biology·R A BlakeS A Courtneidge
Jun 8, 2006·Annual Review of Biochemistry·Alexander Levitzki, Eyal Mishani
Aug 27, 2011·Circulation Research·Rasa TamosiunieneMark R Nicolls
Jun 15, 2013·Beilstein Journal of Organic Chemistry·Sandeep KumarVishnu Ji Ram
Mar 16, 2007·Proceedings of the National Academy of Sciences of the United States of America·Jennifer L Warner-Schmidt, Ronald S Duman
Apr 1, 2014·European Journal of Medicinal Chemistry·Dong-Guk KimByeong-Seon Jeong
Jun 7, 2014·European Journal of Medicinal Chemistry·Long ZhangChuanwen Fan
Apr 22, 2014·European Journal of Medicinal Chemistry·Ângelo MonteiroMaria M M Santos
Aug 16, 2012·Molecular Diversity·Gökçe Cihan-Üstündağ, Gültaze Capan

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.