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

Sun, Li; Tran, Ngoc Quang; Tang, Flora; App, Harald; Hirth, Peter; McMahon, Gerald; Tang, Cho

doi:10.1021/jm980123i

Cited by 477 publications

(367 citation statements)

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“…Under light illumination, SU4312 interchanged freely between the cis-and trans-forms in solution. These forms of SU4312 selectively inhibit VEGFR-2 with IC50 values of 0.8 (cis-form) and 5.2 (trans-form) mM respectively (Sun et al, 1998). Our results showed that SU4312, even at a concentration as high as 30 mM, did not induce any neurotoxicity in primary neuron cultures or in zebrafish.…”

Section: Discussionmentioning

confidence: 61%

“…benzylidenyl]indolin-2-one) is a cell-permeable, potent and selective inhibitor of the VEGF receptor-2 (VEGFR-2) tyrosine kinase that has been designed as a candidate drug for cancer therapy (Sun et al, 1998). SU4312 competes with ATP for binding to VEGFR-2 and is able to completely block VEGF signalling in a noncompetitive manner (Sun et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

“…SU4312 competes with ATP for binding to VEGFR-2 and is able to completely block VEGF signalling in a noncompetitive manner (Sun et al, 1998). SU4312 specifically inhibited VEGF-dependent angiogenesis without damaging normal cells (Tran et al, 2007;Miki et al, 2010) and also reduced the proliferation of multiple myeloma and leukaemia tumour cells in vitro (McMillin et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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The anti‐cancer agent SU4312 unexpectedly protects against MPP⁺‐induced neurotoxicity via selective and direct inhibition of neuronal NOS

Cui

Zhang

et al. 2013

British J Pharmacology

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BACKGROUND AND PURPOSESU4312, a potent and selective inhibitor of VEGF receptor-2 (VEGFR-2), has been designed to treat cancer. Recent studies have suggested that SU4312 can also be useful in treating neurodegenerative disorders. In this study, we assessed neuroprotection by SU4312 against 1-methyl-4-phenylpyridinium ion (MPP + )-induced neurotoxicity and further explored the underlying mechanisms. EXPERIMENTAL APPROACHMPP + -treated neurons and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated zebrafish were used to study neuroprotection by SU4312. NOS activity was assayed in vitro to examine direct interactions between SU4312 and NOS isoforms. KEY RESULTSSU4312 unexpectedly prevented MPP + -induced neuronal apoptosis in vitro and decreased MPTP-induced loss of dopaminergic neurons, reduced expression of mRNA for tyrosine hydroxylase and impaired swimming behaviour in zebrafish. In contrast, PTK787/ZK222584, a well-studied VEGFR-2 inhibitor, failed to prevent neurotoxicity, suggesting that the neuroprotective actions of SU4312 were independent of its anti-angiogenic action. Furthermore, SU4312 exhibited non-competitive inhibition of purified neuronal NOS (nNOS) with an IC50 value of 19.0 mM but showed little or no effects on inducible and endothelial NOS. Molecular docking simulations suggested an interaction between SU4312 and the haem group within the active centre of nNOS. CONCLUSIONS AND IMPLICATIONSU4312 exhibited neuroprotection against MPP + at least partly via selective and direct inhibition of nNOS. Because SU4312 could reach the brain in rats, our study also offered a support for further development of SU4312 to treat neurodegenerative disorders, particularly those associated with NO-mediated neurotoxicity. Abbreviations

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Section: Discussionmentioning

confidence: 61%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The anti‐cancer agent SU4312 unexpectedly protects against MPP⁺‐induced neurotoxicity via selective and direct inhibition of neuronal NOS

Cui

Zhang

et al. 2013

British J Pharmacology

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“…e-mail: furuta@gifu-u.ac.jp forded the condensation products 3 as E/Z mixtures. 12,19) Subsequent reduction of 3 produced the desired saturated products 5 in racemic forms. Related 3-heteroarylmethyl analogs 6-10 were likewise prepared using the corresponding heteroaromatic aldehydes at the condensation stage.…”

Section: Resultsmentioning

confidence: 99%

“…11) However, further study has been suspended, because such compounds were already known as potent inhibitors for receptor tyrosine kinases. [12][13][14] Meanwhile, recent studies reported that rasagiline 4, a therapeutic agent for Parkinson's disease, exhibits a neuroprotective activity through not yet fully solved mechanism, 15,16) besides its primary activity for monoamine oxidase-B inhibition. 17) Compound 4 has no electrophilic moiety to form a covalent bond with thiol groups, suggesting a non-covalent mechanism for the activity.…”

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confidence: 99%

Synthesis of 3-Arylmethyl-2-oxindole Derivatives and Their Effects on Neuronal Cell Death

Furuta

Mizuno

Maeda

et al. 2017

CHEMICAL & PHARMACEUTICAL BULLETIN

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Various 3-arylmethyl-2-oxindole derivatives were synthesized by the Knoevenagel condensation of oxindole and aromatic aldehydes followed by palladium-mediated hydrogenation or hydride-reduction. Further substituted derivatives at C-3 and/or N-1 of the oxindole skeleton were prepared from the condensation products. Their protective effect against neuronal cell death induced by oxidative stress was evaluated by lactate dehydrogenase assay. A structure-activity relationship study revealed that compounds with any of the dialkylamino, nitro or hydroxy groups on the 3-arylmethyl moieties elicit a superior potency to suppress cell death, while others are ineffective. Substitutions with less polar functional groups on the benzene or lactam ring of the oxindole skeleton positively, but not remarkably, affect the potency. In addition, the stereochemistry at C-3 of the oxindole core was not a crucial factor for the neuroprotective activity of the compounds.Key words oxindole derivative; synthesis; structure-activity relationship (SAR); neuronal cell death; oxidative stressLoss of neurons in specific areas of the brain due to neuronal cell death is a common feature of neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. 1,2) Intracellular oxidative stress and endoplasmic reticulum (ER) stress are generally considered to play important roles in the death of neuronal cells. [3][4][5][6] In this context, the agents alleviating the oxidative and ER stresses and restore cellular homeostasis are expected to be potential therapeutic candidates for neurodegenerative diseases.In our continuous studies to elaborate small molecules with neuroprotective activities, we previously reported the design, synthesis and action mechanisms of artificial cyclopentenonetype prostaglandin analogs 1 and 2 7-10) (Fig. 1). These compounds exert their effects through covalent bond formation between the electrophilic conjugated-enone moiety and a cysteine residue of the target proteins, such as Keap1. 7,10) Unfortunately, these compounds induced cell death at higher doses presumably due to non-specific bindings to various proteins. 9) Strongly electrophilic compounds are known to inhibit the function of several proteins having cysteine residues and contribute to cell death. One possible approach to avoid this cytotoxic effect of the electrophilic compounds is to synthesize molecules of moderate electrophilicity. Based on this idea, we designed an α,β-unsaturated oxindole structure 3 (Fig. 2) in which the variable substituent Z can modulate the electrophilicity of the double bond. A preliminary study showed that some of the compounds 3, as expected, suppressed the oxidative stress-induced neuronal cell death without any cytotoxic effect. 11) However, further study has been suspended, because such compounds were already known as potent inhibitors for receptor tyrosine kinases. [12][13][14] Meanwhile, recent studies reported that rasagiline 4, a therapeutic agent for Parkinson's disease, exhibits a neuroprotective activity through not...

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ATP site-directed competitive and irreversible inhibitors of protein kinases

2000

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Several tyrosine and serine/threonine protein kinases have emerged in the last few years as attractive targets in the search for new therapeutic agents being applicable in many different disease indications. Initially, inhibition of these protein kinases by ATP site‐directed inhibitors was considered less prone to success, but medicinal chemists from both academia and industry have been able to impart potency and selectivity to a limited number of scaffolds by modulating and fine‐tuning the interactions of the modified template with the ATP binding site of the selected kinase. The chemical templates that have been used in the synthesis of ATP site‐directed protein kinase inhibitors are reviewed with emphasis on the kinase inhibitors that have entered or are about to enter clinical trials. Examples have been selected to illustrate how structure‐based design approaches and new methods to increase compound diversity have had an impact on this area of research. © 2000 John Wiley & Sons, Inc. Med Res Rev, 20, No. 1, 28–57, 2000

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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

Cited by 477 publications

References 18 publications

The anti‐cancer agent SU4312 unexpectedly protects against MPP⁺‐induced neurotoxicity via selective and direct inhibition of neuronal NOS

The anti‐cancer agent SU4312 unexpectedly protects against MPP⁺‐induced neurotoxicity via selective and direct inhibition of neuronal NOS

Synthesis of 3-Arylmethyl-2-oxindole Derivatives and Their Effects on Neuronal Cell Death

ATP site-directed competitive and irreversible inhibitors of protein kinases

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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

Cited by 477 publications

References 18 publications

The anti‐cancer agent SU4312 unexpectedly protects against MPP+‐induced neurotoxicity via selective and direct inhibition of neuronal NOS

The anti‐cancer agent SU4312 unexpectedly protects against MPP+‐induced neurotoxicity via selective and direct inhibition of neuronal NOS

Synthesis of 3-Arylmethyl-2-oxindole Derivatives and Their Effects on Neuronal Cell Death

ATP site-directed competitive and irreversible inhibitors of protein kinases

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Product

Resources

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The anti‐cancer agent SU4312 unexpectedly protects against MPP⁺‐induced neurotoxicity via selective and direct inhibition of neuronal NOS

The anti‐cancer agent SU4312 unexpectedly protects against MPP⁺‐induced neurotoxicity via selective and direct inhibition of neuronal NOS