Synthesis of Novel Nilotinib Analogues and Biological Evaluation of Their Antiplatelet Activity and Functionality...

Area of Science:

• Medicinal Chemistry
• Oncology
• Pharmacology

Background:

• Nilotinib is a second-generation tyrosine kinase inhibitor used for chronic myelogenous leukemia (CML).
• It targets Bcr-Abl tyrosine kinase activity and proliferation of Bcr-Abl-expressing cells and other malignancies.
• There is a need for novel tyrosine kinase inhibitors with enhanced therapeutic profiles.

Purpose of the Study:

• To synthesize and characterize new nilotinib analogues.
• To evaluate the antiplatelet activity of these analogues.
• To assess their antitumor effects, including effects on cell cycle, apoptosis, and metastasis.

Main Methods:

• Synthesis and full characterization of novel nilotinib analogues.
• Platelet aggregation assays.
• Evaluation of P-selectin, PAC-1, E-cadherin, and N-cadherin expression.
• Assessment of endothelial cell proliferation and cancer cell cycle, apoptosis, and migration.

Main Results:

• Analogues significantly inhibited platelet aggregation compared to nilotinib.
• Analogues strongly inhibited P-selectin and PAC-1 expression upon activation.
• Analogues induced mitosis arrest in HepG2 cells, with analogue-1 showing potent apoptosis induction; none induced HUVEC apoptosis.
• Analogues reduced E-cadherin and N-cadherin expression, with analogues-1 and -3 demonstrating antimigratory effects on HepG2 cells.

Conclusions:

• The synthesized nilotinib analogues possess significant antiplatelet and antitumor properties.
• These novel compounds demonstrate potential for developing improved tyrosine kinase inhibitors.
• Further research may lead to new therapeutic agents for CML and other cancers.