Flavonoids with an oligopolysulfated moiety: a new class of anticoagulant agents.
Polysulfated (oligo)flavonoids were synthesized and assayed for their in vitro and in vivo anticoagulant activities. The approach was based on molecular hybridization of two classes of anticoagulants, sulfated polysaccharides and sulfated flavonoids. The synthesis was optimized using microwave-assisted sulfation with triethylamine-sulfur trioxide. The obtained polysulfated flavonosides were highly effective in increasing clotting times and able to completely block the clotting process, in contrast to their corresponding aglycones. The thromboelastography proved that polysulfated flavonosides possess good whole blood anticoagulation activity. The following structure-activity relationships were found: 3-O-rutinosides (10, 13) were direct inhibitors of FXa, while 7-O-rutinosides (7, 8) showed inhibition of FXa by ATIII activation. Furthermore, compounds 7 and 13 were stable in plasma and active in vivo and preliminary toxicity studies would lead us to rule out acute side effects. From the overall results, the polysulfated flavonosides showed the potential as new effective and safe agents for anticoagulant therapy.
Centro de Química Medicinal-Universidade do Porto (CEQUIMED-UP), Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal.
Marta
M
Correia-da-Silva
Emília
E
Sousa
Bárbara
B
Duarte
Franklim
F
Marques
Félix
F
Carvalho
Luís M
LM
Cunha-Ribeiro
Madalena M M
MM
Pinto
D000328:Adult; D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000990:Antithrombin III / Q000037:antagonists & inhibitors; D065427:Factor Xa Inhibitors; D005419:Flavonoids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005960:Glucosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008875:Middle Aged; D010314:Partial Thromboplastin Time; D010974:Platelet Aggregation / Q000187:drug effects; D011517:Prothrombin Time; D012431:Rutin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013463:Sulfuric Acid Esters / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013916:Thrombelastography; D013917:Thrombin / Q000037:antagonists & inhibitors; D013918:Thrombin Time; D055815:Young Adult
D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D005419:Flavonoids; D005960:Glucosides; D013463:Sulfuric Acid Esters; D012431:Rutin; D000990:Antithrombin III; D013917:Thrombin