Structure, stability, and antiplatelet activity of O-acyl derivatives of salicylic acid and lipophilic esters of acetylsalicylate

• Published in: Pharmacological reports 2009-05, Vol.61 (3), p.476-489
• Main Authors: Zavodnik, Ilya B., Lapshina, Elena, Sudnikovich, Elena, Boncler, Magdalena, Luzak, Bogusława, Różalski, Marcin, Helińska, Magdalena, Watała, Cezary
• Format: Article
• Language: English
• Subjects: acetylsalicylic acid; Aspirin - analogs & derivatives; Aspirin - chemistry; Aspirin - pharmacology; Drug Safety and Pharmacovigilance; Drug Stability; Esters - pharmacology; Humans; In Vitro Techniques; lipophilic esters of acetylsalicylate; Molecular Structure; O-acyl derivatives of salicylic acid; P-Selectin - antagonists & inhibitors; Pharmacotherapy; Pharmacy; platelet aggregation; Platelet Aggregation - drug effects; platelet protein acylation; Protein Binding; Salicylic Acid - chemistry; Salicylic Acid - pharmacology; Structure-Activity Relationship; thromboxane generation; Thromboxanes - biosynthesis
• ISSN: 1734-1140; 2299-5684
• DOI: 10.1016/S1734-1140(09)70089-1

The anti-thrombotic activity of acetylsalicylic acid (ASA) has been shown to be due to specific irreversible acetylation of blood platelet cyclooxygenase. The aim of our study was to investigate the associations between the antiplatelet activities of derivatives of both ASA and salicylic acid (SA), as well as the structure, stability, and molecular properties of these compounds. Homologous series of O-acyl derivatives of salicylic acid (propionyl-, butyrylsalicylic acids, PSA, BSA) and lipophilic dodecyl (C12)-, hexadecyl (C16)-, and cholesteryl acetylsalicylates were synthesized and tested for structure-activity relationships. The molecular properties (heat of formation, molecular surface area, dipole moment) of ASA and SA derivatives obtained by theoretical calculations changed with the increasing length of the acyl or alkyl residue. The inhibition of whole blood platelet aggregation and the reduction in thromboxane (TX) generation by O-acyl derivatives were concentration-dependent and decreased along with increasing the length of acyl chain. These effects correlated with the extent of platelet reactivity and P-selectin expression inhibition in collagen-activated platelets. In contrast to ASA and O-acyl derivatives of SA, none of the lipophilic ASA derivatives had a significant inhibitory effect on platelet aggregation. In conclusion, all SA and ASA derivatives studied under in vitro conditions showed much lower antiplatelet activities than ASA itself, despite their higher affinity to plasma proteins or membrane components and their equivalent ability to acetylate protein free amino groups.We suggest the significance of the carboxylic group, dipole moment, geometry, and size of these pharmaceuticals in their ability to bind to the active site of cyclooxygenase and their antiplatelet efficacy.