Synthesis and Biological Evaluation of Oxindole Sulfonamide Derivatives as Bruton's Tyrosine Kinase Inhibitors
Language English Country Germany Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
Grant support
DST-SERB-EDCR/2016/000288
Department of Science and Technology, India
LM2023052
CZ-OPENSCREEN
LM2023053
EATRIS-CZ
LX22NPO5102
National Institute for Cancer Research
LX22NPO5107
National Institute for Neurological Research
Ministry of Education, Youth and Sports of the Czech Republic (MEYS)
- Keywords
- Antiproliferation, B-cell malignancies, Bruton's tyrosine kinase, Cytotoxicity, Knoevenagel condensation, Oxindole sulfonamide,
- MeSH
- Burkitt Lymphoma * drug therapy MeSH
- Protein Kinase Inhibitors MeSH
- Tyrosine Kinase Inhibitors * MeSH
- Humans MeSH
- Agammaglobulinaemia Tyrosine Kinase MeSH
- Sulfonamides pharmacology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Protein Kinase Inhibitors MeSH
- Tyrosine Kinase Inhibitors * MeSH
- Agammaglobulinaemia Tyrosine Kinase MeSH
- Sulfonamides MeSH
Bruton's tyrosine kinase (BTK) is a promising molecular target for several human B-cell-related autoimmune disorders, inflammation, and haematological malignancies. The pathogenic alterations in various cancer tissues depend on mutant BTK for cell proliferation and survival, and BTK is also overexpressed in a range of hematopoietic cells. Due to this, BTK is emerging as a potential drug target to treat various human diseases, and several reversible and irreversible inhibitors have been developed and are being developed. As a result, BTK inhibition, clinically validated as an anticancer treatment, is finding great interest in B-cell malignancies and solid tumours. This study focuses on the design and synthesis of new oxindole sulfonamide derivatives as promising inhibitors of BTK with negligible off-target effects. The most cytotoxic compounds with greater basicity were PID-4 (2.29±0.52 μM), PID-6 (9.37±2.47 μM), and PID-19 (2.64±0.88 μM). These compounds caused a selective inhibition of Burkitt's lymphoma RAMOS cells without significant cytotoxicity in non-BTK cancerous and non-cancerous cell lines. Further, PID-4 showed promising activity in inhibiting BTK and downstream signalling cascades. As a potent inhibitor of Burkitt's lymphoma cells, PID-4 is a promising lead for developing novel chemotherapeutics.
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