Abstract
Type 2 diabetes mellitus (T2DM) is a multi-factorial disease which can cause multiple organ dysfunction, including that of the vascular endothelium. The aim of the present study was to evaluate the effects of metformin, and its sulfenamide and sulfonamide derivatives (compounds 1–8) on the selected markers of endothelial function and blood coagulation. The integrity of endothelial cells(ECs) was examined using the real-time cell electric impedance system. Tissue Factor(TF) production, the release of von Willebrand Factor (vWF) and tissue plasminogen activator(t-PA) from ECs were determined using immunoenzymatic assays, while the process of platelet thrombus formation using the Total Thrombus-Formation Analysis System. Sulfenamide with n-butyl alkyl chain(3) does not interfere with ECs integrity, and viability (nCI(24h) = 1.03 ± 0.03 vs. 1.06 ± 0.11 for control), but possesses anticoagulation properties manifested by prolonged platelet-dependent thrombus formation (Occlusion Time 370.3 ± 77.0 s vs. 286.7 ± 65.5 s for control) in semi-physiological conditions. Both p- and o-nitro-benzenesulfonamides (compounds7,8) exhibit anti-coagulant properties demonstrated by decreased vWF release and prolonged parameters of platelet thrombus formation and total blood thrombogenicity. In conclusion, chemical modification of metformin scaffold into sulfenamides or sulfonamides might be regarded as a good starting point for the design and synthesis of novel biguanide-based compounds with anticoagulant properties and valuable features regarding endothelial function.
Highlights
UKPDS follow-up study indicated that the cardiovascular risk continued to fall after the study[8]
Upon the stimulation with metformin over the entire concentration range (Figs 2a, 3a, Supplementary Table S1) the normalized cell index of the human umbilical vein endothelial cells (HUVECs) increased with regard to that of untreated cells up to 12 hours
Within this paper we evaluated the effects of metformin, and its sulfenamide and sulfonamide analogues on a few markers of endothelial function and blood coagulation
Summary
UKPDS follow-up study indicated that the cardiovascular risk continued to fall after the study[8]. 12-week administration of metformin at a dose of 2550 mg per day contributed to a reduction of PAI-1 levels (200.7 ng/mL at baseline versus 173.7 ng/mL after 12 weeks)[15] Despite all these beneficial pharmacological activities metformin is characterized by unfavourable pharmacokinetic properties. Our recent in vitro studies[16,17,18] of metformin and its sulfenamide and sulfonamide derivatives have shown that some of the tested biguanides are characterized by beneficial properties with regard to plasma haemostasis, which is frequently impaired in T2DM patients. The results of one clinical trial have shown treatment with metformin to be associated with improvement in some markers of endothelial functions, including von Willebrand factor (vWF) and vascular cell adhesion molecule 1 (VCAM-1)[21]. The final part of the current paper estimates the influence of metformin derivatives on the platelet thrombus formation, and the blood coagulation
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