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

Heart beat relies on coordinated calcium regulation through RyR2 and SERCA2a activity, as well as impulse propagation mediated by Na_V1.5 activity. Here, we present small molecules combining a 1,4-benzothia- or 1,4-benzoxazepine scaffold and a 3-(3,4-dihydroxyphenyl)-2-propenoic acid residue of which five compounds (4, 9, 10, 12, and 13) reduced cardiac RyR2 activity and stimulated SERCA2a activity in our cell systems. The acceleration of SERCA2 activity was particularly enhanced by cyanoborane derivatives 11-13. The substantial impact on SERCA2 activation relates to the presence of polar (zwitterionic) N-B fragments, which can increase the binding affinity to SERCA2 and result in a more efficient activation. Compounds 12 and 13 at a concentration of 10 μM additionally reduced Na_V1.5 activity in Chinese hamster ovary (CHO) cells, indicating a multitargeted drug property. We propose that the multitargeted actions of these novel compounds have the potential to enhance heart failure therapy, particularly in personalized treatment approaches.