Synthesis and Hemostatic Activity of New Amide Derivatives

Abstract

Eight dipeptides containing antifibrinolytic agents (tranexamic acid, aminocaproic acid, 4-(aminomethyl)benzoic acid, and glycine—natural amino acids) were synthesized in a three-step process with good or very good yields. DMT/NMM/TsO− (4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium toluene-4-sulfonate) was used as a coupling reagent. Hemolysis tests were used to study the effects of the dipeptides on blood components. Blood plasma clotting tests were used to examine their effects on thrombin time (TT), prothrombin time (PT), and the activated partial thromboplastin time (aPTT). The level of hemolysis did not exceed 1%. In clotting tests, TT, PT, and aPTT did not differentiate any of the compounds. The prothrombin times for all amides 1–8 were similar. The obtained results in the presence of amides 1–4 and 8 were slightly lower than for the other compounds and the positive control, and they were similar to the results obtained for TA. In the case of amide 3, a significantly decreased aPTT was observed. The aPTTs observed for plasma treated with amide 3 and TA were comparable. In the case of amide 6 and 8, TT values significantly lower than for the other compounds were found. The clot formation and fibrinolysis (CFF) assay was used to assess the influence of the dipeptides on the blood plasma coagulation cascade and the fibrinolytic efficiency of the blood plasma. In the clot formation and fibrinolysis assay, amides 5 and 7 were among the most active compounds. The cytotoxicity and genotoxicity of the synthesized dipeptides were evaluated on the monocyte/macrophage peripheral blood cell line. The dipeptides did not cause hemolysis at any concentrations. They exhibited no significant cytotoxic effect on SC cells and did not induce significant DNA damage.

Reductive Enzyme Cascades for Valorization of PET Deconstruction Products

“…Lastly, we took advantage of the wide substrate scope of both srCAR and cvTA to design an enzyme cascade for the synthesis of monofunctionalized amine, pAMBA, an antifibrinolytic drug. 26 We had previously observed selective reduction of MHET to MHE-4FBA by srCAR ( Fig. 3D, Fig.…”

“…24,25 While diamines can be used as value-added monomers, a significant opportunity exists for the valorization of PET-derived monomers to mono-amines such as para -(aminomethyl)benzoic acid (pAMBA), an antifibrinolytic drug used to promote blood clotting and treat fibrotic skin conditions. 26 Monofunctional molecules are often challenging to make from bifunctional substrates ( e.g., TPA), resulting in poor atom economy and low selectivity. 27 However, enzymatic PET deconstruction offers a previously untapped potential to leverage substrates like MHET, a unique carboxylate with a ester “protecting” group, which could allow for monofunctionalization of terephthalate.…”

Reductive Enzyme Cascades for Valorization of Polyethylene Terephthalate Deconstruction Products

“…Lastly, we took advantage of the wide substrate scope of both srCAR and cvTA to design an enzyme cascade for the synthesis of monofunctionalized amine, pAMBA, an antifibrinolytic drug . We had previously observed selective reduction of MHET to MHE-4FBA by srCAR (Figures D and B).…”

“…Lastly, we took advantage of the wide substrate scope of both srCAR and cvTA to design an enzyme cascade for the synthesis of monofunctionalized amine, pAMBA, an antifibrinolytic drug. 26 We had previously observed selective reduction of MHET to MHE-4FBA by srCAR (Figures 3D and 4B). Owing to the wide substrate scope of cvTA and the previous result that cvTA is highly active on a structurally similar aldehyde, 4FBA, we posited that MHE-4FBA can also be accepted as a substrate by cvTA.…”

Efficacy and safety of tranexamic acid for patients with intertrochanteric fractures treated with intramedullary fixation: A systematic review and meta-analysis of current evidence in randomized controlled trials

“…In recent years, more and more researchers utilized TXA as a promising therapy for perioperative blood control. Transient activation of the fibrinolytic cascade during surgery is one of the reasons for high perioperative blood loss ( Banach et al, 2022 ). TXA can prevent fibrinolysis by blocking the lysine-binding site of plasminogen bound to fibrin and displacing plasminogen from the surface of fibrin ( Tanaka et al, 2001 ).…”