Multitargeted Caffeic Acid Derivatives Inhibit Cardiac RyR2- and Na_V1.5- Channels but Stimulate SERCA2a Pump...

Area of Science:

• Cardiovascular Pharmacology
• Medicinal Chemistry
• Molecular Cardiology

Background:

• Heart function depends on precise calcium handling via RyR2 and SERCA2a, and electrical impulse propagation by Na_V1.5.
• Dysregulation of these ion channels is implicated in heart failure pathogenesis.

Purpose of the Study:

• To design and synthesize novel small molecules targeting key cardiac ion channels.
• To evaluate the efficacy of these compounds in modulating RyR2, SERCA2a, and Na_V1.5 activity.
• To explore their potential as therapeutic agents for heart failure.

Main Methods:

• Synthesis of 1,4-benzothia-/benzoxazepine scaffolds coupled with 3-(3,4-dihydroxyphenyl)-2-propenoic acid residues.
• Cell-based assays to assess effects on cardiac RyR2, SERCA2a, and Na_V1.5 activity.
• Structure-activity relationship analysis focusing on polar N-B fragments.

Main Results:

• Five compounds (4, 9, 10, 12, 13) inhibited RyR2 and stimulated SERCA2a activity.
• Cyanoborane derivatives (11-13) showed enhanced SERCA2a activation due to polar N-B fragments.
• Compounds 12 and 13 also reduced Na_V1.5 activity, indicating multitargeted effects.

Conclusions:

• Novel multitargeted compounds effectively modulate cardiac ion channel activity.
• These compounds hold promise for improving heart failure therapy, potentially via personalized medicine approaches.
• Further investigation into their therapeutic potential is warranted.