Characterization of the plasma and blood anticoagulant potential of structurally and mechanistically novel oligomers of 4-hydroxycinnamic acids

Abstract

Recently, we designed sulfated dehydropolymers (DHPs) of 4-hydroxycinnamic acids that displayed interesting anticoagulant properties. Structurally and mechanistically, sulfated DHPs are radically different from all the anticoagulants studied to date. To assess whether their unique mechanism and structure is worth exploiting for further rational design of homogeneous DHP-based molecules, we investigated their anticoagulant potential in human plasma and blood using a range of clotting assays. Sulfated DHPs prolong plasma clotting times, prothrombin and activated partial thromboplastin times at concentrations comparable to the clinically used low-molecular-weight heparin, enoxaparin. Fibrin formation studies on human plasma show that there is a structural dependence of anticoagulant action. Human whole blood studies using thromboelastography and hemostasis analysis system indicate that they are 17–140-fold less potent than enoxaparin. Results demonstrate that sulfated DHPs possess good in-vitro and ex-vivo activity, which will likely be improved through a rational design.

Gum resin of Boswellia serrata inhibited human monocytic (THP-1) cell activation and platelet aggregation

“…Inhibition of platelet aggregation and enhancing coagulation time can help to a great extent in the management of atherosclerosis (Ross, 1999). Alternative drugs to heparin are of great interest in view of its limitations and allergic problems (Henry et al, 2009). Therefore, efforts on identifying factor Xa inhibitors (Pinto Donald et al, 2010) and screening herbal resources possessing significant antithrombotic activity with minimal side effects are highly essential (Winston, 1999;Kim et al, 2010).…”

Sulfated, low molecular weight lignins inhibit a select group of heparin-binding serine proteases

“…To develop better molecules as regulators of coagulation, we recently designed structural variants of lignin, a naturally occurring biopolymer, as functional macromolecular mimetics of LMWHs [4–6]. These designed oligomers, referred to as sulfated low molecular weight lignins (LMWLs), are polydisperse and heterogeneous preparations in a manner similar to LMWHs.…”

Sulfated, low-molecular-weight lignins are potent inhibitors of plasmin, in addition to thrombin and factor Xa: Novel opportunity for controlling complex pathologies

“…In fact in terms of structure, sulfated LMWLs are unlike any other class of anticoagulants investigated to-date, including the heparins, the coumarins, the hirudins, the peptidomimetics and the small molecule direct inhibitors. Functionally, the sulfated LMWLs display plasma and blood anticoagulation similar to that of LMW heparins (6,7). Yet mechanistically, the sulfated LMWLs were found to exhibit a novel mechanism of anticoagulation involving an exosite II-mediated allosteric inhibition of thrombin (8).…”