- Photoinduced Isomerization and Hepatoxicities of Semaxanib, Sunitinib and Related 3-Substituted Indolin-2-ones
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3-Substituted indolin-2-ones are an important class of compounds that display a wide range of biological activities. Sunitinib is an orally available multiple tyrosine kinase inhibitor that has been approved by the US Food and Drug Administration (FDA) for the treatment of renal cell cancer. Sunitinib and a related compound, semaxanib, exist as thermodynamically stable Z isomers, which photoisomerize to E isomers in solution. In this study, 17 3-substituted indolin-2-ones were synthesized, and the kinetics of their photoisomerization were studied by 1H NMR spectroscopy. The rate constants for photoisomerization ranged from 0.009 to 0.048 h-1. Selected compounds were tested for cytotoxicity in the TAMH liver cell line. E/Z mixtures of four compounds were also assessed for toxicity in the TAMH and HepG2 cell lines. In some cases, the stereochemically pure drug was more toxic than the E/Z mixtures, but a general statement cannot be made. Our studies show that each stereoisomer could contribute differently to toxicity, suggesting that stereochemical purity issues that could arise from isomerization cannot be ignored.
- Ngai, Mun Hong,So, Choon Leng,Sullivan, Michael B.,Ho, Han Kiat,Chai, Christina L. L.
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- Prototyping kinase inhibitor-cytotoxin anticancer mutual prodrugs activated by tumour hypoxia: A chemical proof of concept study
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Amide- and ester-linked kinase inhibitor-cytotoxin conjugates were rationally designed and synthesised as prototype hypoxia-activated anticancer mutual prodrugs. Chemical reduction of an aryl nitro trigger moiety was shown to initiate a spontaneous cyclis
- Sansom, Geraud N.,Kirk, Nicholas S.,Guise, Christopher P.,Anderson, Robert F.,Smaill, Jeff B.,Patterson, Adam V.,Kelso, Michael J.
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- Facile synthesis of various nitro-substituted derivatives of Semaxinib (SU5416)
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The synthesis of novel nitro-substituted derivatives of the tyrosine kinase inhibitor Semaxinib (SU5416) is described. The reaction of various substituted oxindoles with 3,5-dimethylpyrrol-2-carbaldehyde derivatives under Knoevenagel conditions gave an array of nitro-substituted derivatives of Semaxinib (SU5416) in high yields of 72-87%. Copyright Taylor & Francis Group, LLC.
- Kniess, Torsten,Kuchar, Manuela,Wuest, Frank
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- Discovery of hybrids of indolin-2-one and nitroimidazole as potent inhibitors against drug-resistant bacteria
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With antibiotics resistance developing rapidly, new antibacterial agents are needed to be discovered. We readily synthesized 11 indolin-2-one compounds and found a hybrid of indolin-2-one and nitroimidazole 3-((1-methyl-5-nitro-1H-imidazol-2-yl)methylene)
- Zhou, Yuanzheng,Ju, Yuan,Yang, Yang,Sang, Zitai,Wang, Zhenling,He, Gu,Yang, Tao,Luo, Youfu
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p. 887 - 897
(2018/07/13)
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- Tandem Horner-Wadsworth-Emmons/Heck procedures for the preparation of 3-alkenyl-oxindoles: The synthesis of Semaxanib and GW441756
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A tandem sequence involving Horner-Wadsworth-Emmons (HWE) olefination followed by a palladium-catalysed intramolecular Heck reaction has been developed to provide rapid access to 3-alkenyl-oxindoles from α-halo-anilides. This one-pot microwave accelerated process proceeds with catalytic palladium(II) acetate or tetrakis(triphenylphosphine)palladium, and has been used to prepare a range of adducts derived from aromatic, heteroaromatic and aliphatic aldehydes. The procedures can be used to prepare N-unprotected oxindoles directly and the applicability of the process has been established by carrying out one-pot syntheses of Semaxanib, an angiogenesis signalling inhibitor, and GW441756, an aza-oxindole Trk A inhibitor.
- Lubkoll, Jana,Millemaggi, Alessia,Perry, Alexis,Taylor, Richard J.K.
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experimental part
p. 6606 - 6612
(2010/10/19)
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- Synthesis of potential prodrug systems for reductive activation. Prodrugs for anti-angiogenic isoflavones and VEGF receptor tyrosine kinase inhibitory oxindoles
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A number of potential prodrug systems for reductive activation have been investigated. The prodrug systems chosen for the study were the 2-nitrophenylacetyl, 3-methyl-3-(3,6-dimethyl-1,4-benzoquinon-2-yl)butanoyl and 4-nitrobenzyl groups, readily attached
- Blanche, Emilie A.,Maskell, Lesley,Colucci, Marie A.,Whatmore, Jacqueline L.,Moody, Christopher J.
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experimental part
p. 4894 - 4903
(2009/11/30)
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- Methods for treating diseases and disorders related to unregulated angiogenesis and/or vasculogenesis
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The present invention relates to methods for treating diseases and disorders related to unregulated angiogenesis and/or vasculogenesis. More specifically, this invention relates to methods for treating diseases and disorders, such as rheumatoid arthritis,
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- 3-(2'-halobenzylidenyl)-2-indolinone compounds for the treatment of disease
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The present invention relates to organic molecules capable of modulating tyrosine kinase signal transduction in order to regulate, modulate and/or inhibit abnormal cell proliferation.
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- 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
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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 rationale to suggest that these compounds may bind in the ATP binding pocket of RTKs. The structure-activity analysis supports the use of subsets of these compounds as specific chemical leads for the development of RTK- specific drugs with broad application for the treatment of human diseases.
- Sun, Li,Tran, Ngoc,Tang, Flora,App, Harald,Hirth, Peter,McMahon, Gerald,Tang, Cho
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p. 2588 - 2603
(2007/10/03)
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