Discovery of Indolinone-Based Multikinase Inhibitors as Potential Therapeutics for Idiopathic Pulmonary Fibrosis

Huang, Zhenhua; Li, Heran; Zhang, Qian; Lu, Fangzheng; Zhang, Zhigang; Guo, Xiaocui; Zhu, Yuanju; Li, Sanming; Liu, Hongzhuo

doi:10.1021/acsmedchemlett.7b00164

Cited by 15 publications

(8 citation statements)

References 13 publications

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“…Several reports on the molecular docking of indolin-2-ones toward the stem cell factor receptor c-KIT are available; ,, hence, in order to investigate the anticancer potential of the molecule designed to target c-KIT, we envisaged the molecular docking pattern of the synthesized indolin-2-ones.…”

Section: Resultsmentioning

confidence: 99%

“…Docking Studies on c-KIT. Several reports on the molecular docking of indolin-2-ones toward the stem cell factor receptor c-KIT are available; 39,45,46 hence, in order to investigate the anticancer potential of the molecule designed to target c-KIT, we envisaged the molecular docking pattern of the synthesized indolin-2-ones. All the synthesized indolin-2-ones were included in an SP mode docking study performed on the c-KIT protein (PDB ID 3G0E) using the GLIDE program.…”

Section: Reaction Kinetics Study Of Thioetherificationmentioning

confidence: 99%

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Discovery and Anticancer Activity of Novel 1,3,4-Thiadiazole- and Aziridine-Based Indolin-2-ones via In Silico Design Followed by Supramolecular Green Synthesis

et al. 2022

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Three crucial anticancer scaffolds, namely indolin-2-one, 1,3,4-thiadiazole, and aziridine, are explored to synthesize virtually screened target molecules based on the c-KIT kinase protein. The stem cell factor receptor c-KIT was selected as target because most U.S. FDA-approved receptor tyrosine kinase inhibitors bearing the indolin-2-one scaffold profoundly inhibit c-KIT. Molecular hybrids of indolin-2-one with 1,3,4-thiadiazole ( IIIa – m ) and aziridine ( VIa and VIc ) were afforded through a modified Schiff base green synthesis using β-cyclodextrin-SO 3 H in water as a recyclable proton-donor catalyst. A computational study found that indolin-2,3-dione forms a supramolecular inclusion complex with β-cyclodextrin-SO 3 H through noncovalent interactions. A molecular docking study of all the synthesized compounds was executed on the c-KIT kinase domain, and most compounds displayed binding affinities similar to that of Sunitinib. On the basis of the pharmacokinetic significance of the aryl thioether linkage in small molecules, 1,3,4-thiadiazole hybrids ( IIIa – m ) were extended to a new series of 3-((5-(phenylthio)-1,3,4-thiadiazol-2-yl)imino)indolin-2-ones ( IVa – m ) via thioetherification using bis(triphenylphosphine)palladium(II)dichloride as the catalyst for C–S bond formation. Target compounds were tested against NCI-60 human cancer cell lines for a single-dose concentration. Among all three series of indolin-2-ones, the majority of compounds demonstrated broad-spectrum activity toward various cancer cell lines. Compounds IVc and VIc were further evaluated for a five-dose anticancer study. Compound IVc showed a potent activity of IC 50 = 1.47 μM against a panel of breast cancer cell lines, whereas compound VIc exhibited the highest inhibition for a panel of colon cancer cell lines at IC 50 = 1.40 μM. In silico ADME property descriptors of all the target molecules are in an acceptable range. Machine learning algorithms were used to examine the metabolites and phase I and II regioselectivities of compounds IVc and VIc , and the results suggested that these two compounds could be potential leads for the treatment of cancer.

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Section: Resultsmentioning

confidence: 99%

Section: Reaction Kinetics Study Of Thioetherificationmentioning

confidence: 99%

Discovery and Anticancer Activity of Novel 1,3,4-Thiadiazole- and Aziridine-Based Indolin-2-ones via In Silico Design Followed by Supramolecular Green Synthesis

et al. 2022

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“…PF is a chronic progressive interstitial lung disease accompanied by the proliferation of myofibroblasts [ 149 ]. Recent studies indicate that ferroptosis in lung tissue promotes the development of PF.…”

Section: Ferroptosis and Lung Diseasementioning

confidence: 99%

Targeting Ferroptosis for Lung Diseases: Exploring Novel Strategies in Ferroptosis‐Associated Mechanisms

Zhou

Wang³

et al. 2021

Oxidative Medicine and Cellular Longevity

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Ferroptosis is an iron-dependent regulated necrosis characterized by the peroxidation damage of lipid molecular containing unsaturated fatty acid long chain on the cell membrane or organelle membrane after cellular deactivation restitution system, resulting in the cell membrane rupture. Ferroptosis is biochemically and morphologically distinct and disparate from other forms of regulated cell death. Recently, mounting studies have investigated the mechanism of ferroptosis, and numerous proteins play vital roles in regulating ferroptosis. With detailed studies, emerging evidence indicates that ferroptosis is found in multiple lung diseases, demonstrating that ferroptosis appears to be particularly important for lung diseases. The mounting interest in ferroptosis drugs specifically targeting the ferroptosis mechanism holds substantial therapeutic promise in lung diseases. The present review emphatically summarizes the functions and integrated molecular mechanisms of ferroptosis in various lung diseases, proposing that multiangle regulation of ferroptosis might be a promising strategy for the clinical treatment of lung diseases.

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“…In a straightforward acylation method, acids or acid chlorides are employed as a source of the acyl group to couple with 2‐oxindole under transition metal‐free conditions with the limited number of substrate scope (Scheme c) . Besides, 2‐oxindoles were condensed with trimethylorthobenzoate in acetic anhydride to provide 3‐alkylideneoxindoles (Scheme d) . The scission and fusion of the C−C bond are one of the fundamental steps explored with great interest both in academics and industry involving transition metal and metal‐free conditions .…”

Section: Figurementioning

confidence: 99%

DBU‐Promoted α‐Acylation of 2‐Oxindoles through Acyl C−C Bond Cleavage: Imidazolium Salts as an Emerging Acylating Agent

2020

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We report a direct and effective metal-free αacylation of 2-oxindoles using C-acyl imidazolium salts as an acylating agent via C(O)À C bond cleavage. The mild reaction conditions, affordable base, additive-free and simple substrates make this methodology very attractive for easy access to 3-alkylidene oxindoles -privilege biologically active oxindole derivatives. The wide substrate scope and gram-scale preparation are notable features of this methodology. 4 5 6 7 8

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Discovery of Indolinone-Based Multikinase Inhibitors as Potential Therapeutics for Idiopathic Pulmonary Fibrosis

Cited by 15 publications

References 13 publications

Discovery and Anticancer Activity of Novel 1,3,4-Thiadiazole- and Aziridine-Based Indolin-2-ones via In Silico Design Followed by Supramolecular Green Synthesis

Discovery and Anticancer Activity of Novel 1,3,4-Thiadiazole- and Aziridine-Based Indolin-2-ones via In Silico Design Followed by Supramolecular Green Synthesis

Targeting Ferroptosis for Lung Diseases: Exploring Novel Strategies in Ferroptosis‐Associated Mechanisms

DBU‐Promoted α‐Acylation of 2‐Oxindoles through Acyl C−C Bond Cleavage: Imidazolium Salts as an Emerging Acylating Agent

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