Centro de Química Medicinal, Universidade do Porto (CEQUIMED-UP), Departamento de Química, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal.
J Med Chem. 2011 Aug 11;54(15):5373-84. doi: 10.1021/jm2006589. Epub 2011 Jul 18.
A multipathway strategy was used to evaluate the in vitro and in vivo antithrombotic effects of a new synthetic family of sulfated small molecules. Polysulfated xanthonosides showed highly effective anticoagulation effects in vitro, both in plasma (clotting times) and in whole human blood (thromboelastography), as well as in vivo (ip administration, mice). Physicochemical properties were assessed for mangiferin heptasulfate (7), which showed high solubility and stability in water and in human plasma and no putative hepatotoxicity in vivo. Mangiferin heptasulfate (7) was found to be a direct inhibitor of FXa, while persulfated 3,6-(O-β-glucopyranosyl)xanthone (13) acted as a dual inhibitor of FXa (directly and by antithrombin III activation). By impedance aggregometry, compounds 7 and 13 exhibited the antiplatelet effect by inhibition of both arachidonic acid and ADP-induced platelet aggregation. Dual anticoagulant/antiplatelet agents, such as sulfated xanthonosides 7 and 13, are expected to lead to a new therapeutic approach for the treatment of both venous and arterial thrombosis.
采用多途径策略评估了一系列新型合成磺酸小分子的体外和体内抗血栓形成作用。多磺酸姜酮苷在体外（血浆（凝血时间）和全血（血栓弹力描记法））以及体内（ip 给药，小鼠）均表现出高度有效的抗凝作用。对芒果苷七硫酸盐（7）进行了理化性质评估，结果表明其在水中和人血浆中具有高溶解度和稳定性，且体内无潜在肝毒性。芒果苷七硫酸盐（7）被发现是 FXa 的直接抑制剂，而多磺酸化 3,6-（O-β-葡萄糖吡喃糖苷基）姜黄素（13）则是 FXa 的双重抑制剂（直接抑制和通过抗凝血酶 III 激活）。通过阻抗聚集测定，化合物 7 和 13 通过抑制花生四烯酸和 ADP 诱导的血小板聚集来发挥抗血小板作用。双重抗凝/抗血小板药物，如磺酸化姜酮苷 7 和 13，有望为静脉和动脉血栓形成的治疗提供新的治疗方法。
