Figure 10.

The chemical structures of flavonoid-based sulfated NSGMs that allosterically inhibit human plasmin and human FXIIIa. Pentasulfated flavonoid-quinazolinone heterodimer 35 was initially discovered as allosteric and marginally selective inhibitor of human plasmin. Subsequent efforts led to the identification of octasulfated flavonoid homodimer 36 inhibited human full-length plasmin with an IC₅₀ value of 7.2 µM (K_D=0.7 µM) and displayed significant selectivity against factors Xa, XIa, IXa, XIIa, trypsin, and chymotrypsin. Sulfated diflavonoid 36 also inhibited the physiologic function of plasmin i.e. clot lysis under physiological conditions in a dose-dependent manner with an IC₅₀ value of 8.8 µM and efficacy of 69%. Interestingly, homologation of the sulfated diflavonoid 36 led to the undecasulfated flavonoid trimer 37 which was the first allosteric inhibitor of FXIIIa, a coagulation transglutaminase. NSGM 37 inhibited FXIIIa with an IC₅₀ value of 36 µM (K_D = 25.3 µM) and efficacy of 98%. The molecule exhibited good selectivity against thrombin, FXa, and papain. It also inhibited the physiological function of FXIIIa as measured by the cross-linking of fibrin monomers.