Effect of mono-guanidine-like derivatives on platelet aggregation and tumour cell induced platelet aggregation†

Abstract

Antiplatelet agents are the cornerstone for the treatment and prevention of cardiovascular diseases. However, they can induce severe side effects such as gastrointestinal bleeding. The main aim of this study is to determine the effect that novel guanidine-based derivatives exert on platelet aggregation. From a screening, in collaboration with the Psychoactive Drug Screening Project service of several compounds from our in-house library of α2-adrenoceptors' ligands, four compounds showed high to medium affinity towards α2C-adrenoceptors and H2 histamine receptors. Based on the structure of these compounds, another two in-house α2-adrenoceptors' ligands were also selected. The effect of the six compounds on platelet aggregation was investigated by light transmission aggregometry and optical microscopy. Flow cytometry was used to analyse their effect on platelet activation by measuring the expression of GPIIb/IIIa and P-selectin platelet receptors. Finally, the potential effect of those compounds on tumour cell-induced platelet aggregation was studied on three cancer cell lines from different origins using optical microscopy. We found that three of these compounds, with very good affinity towards H2 histamine receptors, significantly inhibited platelet aggregation, induced by both ADP and collagen, at the highest concentrations tested, and that tumour cell-induced platelet aggregation was also modulated by these derivatives. Our findings suggest that these aryl guanidine-like systems have an antiplatelet effect that could be also beneficial to reduce tumour cell–platelet interactions.