Synthesis, biological evaluation and molecular docking of new sulfonamide-based indolinone derivatives as multitargeted kinase inhibitors against leukemia

Marwa El-Hussieny; Naglaa F El-Sayed; Marwa A Fouad; Ewies F Ewies

doi:10.1016/j.bioorg.2021.105421

Synthesis, biological evaluation and molecular docking of new sulfonamide-based indolinone derivatives as multitargeted kinase inhibitors against leukemia

Bioorg Chem. 2021 Dec:117:105421. doi: 10.1016/j.bioorg.2021.105421. Epub 2021 Oct 11.

Authors

Marwa El-Hussieny¹, Naglaa F El-Sayed¹, Marwa A Fouad², Ewies F Ewies¹

Affiliations

¹ Organometallic and Organometalloid Chemistry Department, National Research Centre, 33 ElBohouth St., (Former El Tahrir) Dokki, P.O. 12622, Giza, Egypt.
² Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Aini St., Cairo 11562, Egypt; Pharmaceutical Chemistry Department, School of Pharmacy, New Giza University, Newgiza, km 22 Cairo-Alexandria Desert Road, Cairo, Egypt.

PMID: 34666258
DOI: 10.1016/j.bioorg.2021.105421

Abstract

Series of novel sulfonamide-based 3-indolinones 3a-m and 4a-f were designed, synthesized and then their cytotoxic activity was evaluated against a panel of sixty cancer cell lines. This screening indicated that 4-(2-(5-fluoro-2-oxoindolin-3-ylidene)acetyl)phenyl benzenesulfonate (4f) possessed promising cytotoxicity against CCRF-CEM and SR leukemia cell lines with IC₅₀ values 6.84 and 2.97 µM, respectively. Further investigation of the leukemic cytotoxicity of compound 4f was carried out by performing PDGFRα, VEGFR2, Aurora A/B and FLT3 enzyme assays and CCRF-CEM and SR cell cycle analysis. These investigations showed that compound 4f exhibited pronounced dual inhibition of both kinases PDGFRα and Aurora A with potency of 24.15 and 11.83 nM, respectively. The in vitro results were supported by molecular docking studies in order to explore its binding affinity and its key amino acids interactions. This work represents compound 4f as a promising anticancer agent against leukemia.

Keywords: Aurora; Cell cycle arrest; FLT3; Indolinone; Leukemia; PDGFR; Sunitinib.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Molecular Docking Simulation*
Molecular Structure
Oxindoles / chemical synthesis
Oxindoles / chemistry
Oxindoles / pharmacology*
Phosphotransferases / antagonists & inhibitors*
Phosphotransferases / metabolism
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship
Sulfonamides / chemical synthesis
Sulfonamides / chemistry
Sulfonamides / pharmacology*

Substances

Antineoplastic Agents
Oxindoles
Protein Kinase Inhibitors
Sulfonamides
Phosphotransferases