Palmatine Derivatives as Potential Antiplatelet Aggregation Agents via Protein Kinase G/Vasodilator-Stimulated Phosphoprotein and Phosphatidylinositol 3‑Kinase/Akt Phosphorylation

Sixty
palmatine (PMT) derivatives were synthesized and evaluated
for antiplatelet aggregation taking berberine as the lead, and the
structure–activity relationship was first systematically described.
Among them, compound 2v showed the best potency in reducing
adenosine diphosphate (ADP)-induced platelet aggregation in a dose-dependent
manner. It greatly suppressed ADP-induced platelet aggregation, activation,
and Akt phosphorylation in vitro and ex vivo after oral administration
to mice. It also effectively inhibited carrageenan-induced thrombus
formation in the mouse tail and lung, as well as reduced the serum
P-selectin level. Compound 2v might simultaneously bind
to protein kinase G to improve vasodilator-stimulated phosphoprotein
phosphorylation and bind to phosphatidylinositol 3-kinase to inhibit
Akt phosphorylation, which synergically reduced platelet aggregation,
thereby achieving antithrombotic efficacy. Therefore, PMT derivatives
constituted a novel family of antiplatelet aggregation agents with
the advantage of a good safety profile, worthy of further investigation.