Design and synthesis of pyrrole–5-(2,6-dichlorobenzyl)sulfonylindolin-2-ones with C-3′ side chains as potent Met kinase inhibitors

Liu, Chia-Wei; Lai, Chun‐Liang; Lin, Yu‐Hsiang; Teng, Li-Wei; Yang, Sheng-Chuan; Wei, Win-Yin; Lin, Shu Fu; Yang, Ju‐Ying; Huang, Hsin-I; Wang, Ruwen; Chiang, Chien‐Hung; Lee, Mei-Hui; Wang, Yuchuan; Chuang, Shuang‐En; Chang, Jia‐Ming; Lee, Ying-Shuan E.; Huang, Jow Lay

doi:10.1039/c4ra08720h

Cited by 7 publications

(3 citation statements)

References 17 publications

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“…The mixture was heated to 70 °C using an oil bath to afford 2-oxoindoline-5-sulfonyl chloride 2 . , Sulfonyl chloride intermediate 2 was coupled in the presence of pyridine with N -Boc piperazine 3 , , resulting in N -Boc 4-(2-oxoindoline-5-sulfonamido)piperazine 4 . Intermediate 4 in ethanol was subjected to Knoevenagel condensation with cyclopentanone 5 by adding pyrrolidine as a base that affords intermediate 6 . , The protecting group tertiary butyl carbonyl of intermediate 6 was removed by treating it with 4 M HCl in 1,4-dioxane to yield critical scaffold 7 as HCl salt. Analogues 9a – 9j were synthesized by amide coupling with different acid chlorides 8a – 8j in the presence of di-isopropyl ethyl amine.…”

Section: Synthesismentioning

confidence: 99%

“…Intermediate 4 in ethanol was subjected to Knoevenagel condensation with cyclopentanone 5 by adding pyrrolidine as a base that affords intermediate 6 . 26 , 27 The protecting group tertiary butyl carbonyl of intermediate 6 was removed by treating it with 4 M HCl in 1,4-dioxane to yield critical scaffold 7 as HCl salt. Analogues 9a – 9j were synthesized by amide coupling with different acid chlorides 8a – 8j in the presence of di-isopropyl ethyl amine.…”

Section: Synthesismentioning

confidence: 99%

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Novel 5-Substituted Oxindole Derivatives as Bruton’s Tyrosine Kinase Inhibitors: Design, Synthesis, Docking, Molecular Dynamics Simulation, and Biological Evaluation

Velavalapalli,

Maddipati,

Gurská

et al. 2024

ACS Omega

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Bruton's tyrosine kinase (BTK) is a non-RTK cytoplasmic kinase predominantly expressed by hemopoietic lineages, particularly Bcells. A new oxindole-based focused library was designed to identify potent compounds targeting the BTK protein as anticancer agents. This study used rational approaches like structure-based pharmacophore modeling, docking, and ADME properties to select compounds. Molecular dynamics simulations carried out at 20 ns supported the stability of compound 9g within the binding pocket. All the compounds were synthesized and subjected to biological screening on two BTK-expressing cancer cell lines, RAMOS and K562; six non-BTK cancer cell lines, A549, HCT116 (parental and p53 −/− ), U2OS, JURKAT, and CCRF-CEM; and two non-malignant fibroblast lines, BJ and MRC-5. This study resulted in the identification of four new compounds, 9b, 9f, 9g, and 9h, possessing free binding energies of −10.8, −11.1, −11.3, and −10.8 kcal/mol, respectively, and displaying selective cytotoxicity against BTK-high RAMOS cells. Further analysis demonstrated the antiproliferative activity of 9h in RAMOS cells through selective inhibition of pBTK (Tyr223) without affecting Lyn and Syk, upstream proteins in the BCR signaling pathway. In conclusion, we identified a promising oxindole derivative (9h) that shows specificity in modulating BTK signaling pathways.

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Section: Synthesismentioning

confidence: 99%

Section: Synthesismentioning

confidence: 99%

Novel 5-Substituted Oxindole Derivatives as Bruton’s Tyrosine Kinase Inhibitors: Design, Synthesis, Docking, Molecular Dynamics Simulation, and Biological Evaluation

Velavalapalli,

Maddipati,

Gurská

et al. 2024

ACS Omega

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“…By adding pyrrolidine as a base, the intermediate 4 in ethanol was subjected to Knoevenagel condensation with cyclopentanone 5, affording the intermediate 6. [24,25]. The protecting group tertiary butyl carbonyl of intermediate 6 was removed by treating it with 4M HCl in ethyl acetate to yield the critical scaffold 7 as an HCl salt.…”

Section: 3: Synthesismentioning

confidence: 99%

Novel 3-cyclopentylidene-5-(methylsulfonyl)indolin-2-one derivatives as Anti-tubercular Agents: Design, Synthesis, Docking, Molecular Dynamic Simulation, and Biological Evaluation

Velavalapalli,

Kumar,

Katari

et al. 2024

Preprint

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Nearly 3 million people die from tuberculosis (TB), which affects the lungs and other regions of the body. It is the most common bacterial infectious agent. We report the molecular docking, molecular dynamic simulations, synthesis, characterization, and biological activity of indolin-2-one derivatives as a novel anti-mycobacterial series identified from MABA (Microplate Alamar Blue Assay )method. The docking method was employed to investigate the intermolecular interactions between each compound and the enzyme Decaprenyl phosphoryl-D-ribose 2′-epimerase(DprE1). The results revealed significant binding interaction energies between these compounds and the enzyme. The stability of the interaction was evaluated using a standard 20 ns dynamic simulation study. For the protein-ligand complex's stability under the dynamic settings, parameters generated from MD simulation trajectories were computed and validated. The three compounds showed significant anti-mycobacterial activity, with MICs of 3.12 μg/ml against M. tuberculosis. All the compounds have favourable in vitroabsorption-distribution-metabolism-excretion (ADME). Evaluation of all the new compounds for in vitroanti-mycobacterial activity against Mycobacterium tuberculosis H37Rv (ATCC27294) resulted in 9b, 9c, and 15a (MIC: 3.125μg/mL) as promising lead analogues.

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The inhibition profiles of 4'‐acylpyrrole–5‐fluoroindolin‐2‐ones with a C‐3' side chain for VEGFR2, PDGFR‐β, and FGFR‐1 protein kinases

Huang

Lin

Lai

et al. 2020

J Chinese Chemical Soc

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In this study, we reported the inhibition profiles of 4′‐acylpyrrole–5‐fluoroindolin‐2‐one 3 with a C‐3′ side chain for VEGFR2, PDGFR‐β, and FGFR‐1 protein kinases. The pyrrole‐fused cyclohexanone moiety provided 3 with the best potency to inhibit the three kinases, and the C‐3′ side chains contributed to the different inhibition profiles of 3. Compound 3b with a C‐3′ 2‐carboxylethyl side chain showed good potency for the three kinase (IC50: 25–260 nM), and compound 3g with a N,N‐dialkyl‐2‐carbamoylethyl side chain was more active for VEGFR2 (IC50: 59 nM) and PDGFR‐β (IC50: 16 nM) than FGFR‐1 (IC50: 1.7 μM). The C‐3′ 3‐(dialkylamino)propyl side chain accomplished 3h–j as selective PDGFR‐β inhibitors (IC50: 7.8–13 nM). Compound 3b was further investigated and found potent to inhibit VEGF‐ and FGF‐dependent cell proliferation with moderate in vivo anticancer activity. Results from docking simulations revealed that the interactions of 3b with VEGFR2 and FGFR‐1 which could account for the different inhibition profiles of 3.

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Design and synthesis of pyrrole–5-(2,6-dichlorobenzyl)sulfonylindolin-2-ones with C-3′ side chains as potent Met kinase inhibitors

Abstract: Subnanomolar Met inhibitors.

Cited by 7 publications

References 17 publications

Novel 5-Substituted Oxindole Derivatives as Bruton’s Tyrosine Kinase Inhibitors: Design, Synthesis, Docking, Molecular Dynamics Simulation, and Biological Evaluation

Novel 5-Substituted Oxindole Derivatives as Bruton’s Tyrosine Kinase Inhibitors: Design, Synthesis, Docking, Molecular Dynamics Simulation, and Biological Evaluation

Novel 3-cyclopentylidene-5-(methylsulfonyl)indolin-2-one derivatives as Anti-tubercular Agents: Design, Synthesis, Docking, Molecular Dynamic Simulation, and Biological Evaluation

The inhibition profiles of 4'‐acylpyrrole–5‐fluoroindolin‐2‐ones with a C‐3' side chain for VEGFR2, PDGFR‐β, and FGFR‐1 protein kinases

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