Synthesis and evaluation of the platelet antiaggregant properties of phenolic antioxidants structurally related to rosmarinic acid.
Polyphenols, such as rosmarinic acid, are widely distributed natural products with relevant antioxidant activity. Oxidative stress plays an important role in the pathogenesis of a number of disorders. Here, we report on the synthesis and biological effects of the polyphenolic esters hydroxytyrosyl gallate (1), hydroxytyrosyl protocatechuate (2) and hydroxytyrosyl caffeate (3), structurally related to rosmarinic acid. The three compounds showed a greater free radical scavenging activity than their precursors and also than rosmarinic acid. Esters 1 and 3 significantly reduced thrombin-evoked platelet aggregation, which is likely mediated to the attenuation of thrombin-stimulated Ca(2+) release and entry. The three compounds reduced the ability of platelets to accumulate Ca(2+) in the intracellular stores, probably by enhancing the Ca(2+) leakage rate and reduced store-operated Ca(2+) entry in these cells. These observations suggest that the structurally-simplified analogs to rosmarinic acid, compounds 1 and 3, might be the base of therapeutic strategies to prevent thrombotic complications associated to platelet hyperaggregability due to oxidative stress.
Chapado
Laura
L
Department of Inorganic and Organic Chemistry, University of Jaén, Spain. lchapado@ujaen.es
Linares-Palomino
Pablo J
PJ
Salido
Sofía
S
Altarejos
Joaquín
J
Rosado
Juan A
JA
Salido
Ginés M
GM
D000975:Antioxidants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D002109:Caffeic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002934:Cinnamates / Q000737:chemistry*; D053630:Depsides / Q000737:chemistry*; D005707:Gallic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013917:Thrombin / Q000378:metabolism; D000097123:Rosmarinic Acid
D000975:Antioxidants; D002109:Caffeic Acids; D002118:Calcium; D002934:Cinnamates; D053630:Depsides; D005707:Gallic Acid; D010975:Platelet Aggregation Inhibitors; D013917:Thrombin; D000097123:Rosmarinic Acid