Laboratory of Bioanalysis, Department of Pharmaceutical Chemistry, Drug Analysis and Radiopharmacy, Medical University of Lodz, ul. Muszyńskiego1, 90-151 Lodz, Poland.
Department of Bioinorganic Chemistry, Medical University of Lodz, ul. Muszyńskiego1, 90-151 Lodz, Poland.
Int J Mol Sci. 2022 Apr 8;23(8):4132. doi: 10.3390/ijms23084132.
Due to its high efficiency, good safety profile, and potential cardio-protective properties, metformin, a dimethyl biguanide, is the first-line medication in antihyperglycemic treatment for type 2 diabetic patients. The aim of our present study was to assess the effects of eight new sulfonamide-based derivatives of metformin on selected plasma parameters and vascular hemostasis, as well as on endothelial and smooth muscle cell function. The compounds with an alkyl chain (-), trifluoromethyl substituent (), or acetyl group () significantly elevated glucose utilization in human umbilical endothelial cells (HUVECs), similarly to metformin. Our novel findings showed that metformin analogues - presented the most beneficial properties because of their greatest safety profile in the WST-1 cell viability assay, which was also proved in the further HUVEC integrity studies using RTCA DP. Compounds - did not affect either HUVEC or aortal smooth muscle cell (AoSMC) viability up to 3.0 mM. Importantly, these compounds beneficially affected some of the coagulation parameters, including factor X and antithrombin III activity. In contrast to the above-mentioned metformin analogues, derivatives and exerted more profound anticoagulation effects; however, they were also more cytotoxic towards HUVECs, as IC values were 1.0-1.5 mM. In conclusion, the chemical modification of a metformin scaffold into sulfonamides possessing alkyl substituents results in the formation of novel derivatives with potential bi-directional activity including anti-hyperglycemic properties and highly desirable anti-coagulant activity.
由于其高效、良好的安全性和潜在的心脏保护特性，二甲双胍作为一种双胍类药物，是 2 型糖尿病患者抗高血糖治疗的一线药物。我们目前的研究旨在评估 8 种新型磺酰胺类二甲双胍衍生物对选定的血浆参数和血管止血以及内皮和平滑肌细胞功能的影响。具有烷基链 (-)、三氟甲基取代基 () 或乙酰基 () 的化合物与二甲双胍相似，显著提高了人脐静脉内皮细胞 (HUVEC) 的葡萄糖利用率。我们的新发现表明，由于在 WST-1 细胞活力测定中具有最大的安全性，二甲双胍类似物 - 具有最有益的特性，这在进一步使用 RTCA DP 进行的 HUVEC 完整性研究中也得到了证明。化合物 - 直到 3.0 mM 也不会影响 HUVEC 或主动脉平滑肌细胞 (AoSMC) 的活力。重要的是，这些化合物有益地影响了一些凝血参数，包括因子 X 和抗凝血酶 III 活性。与上述二甲双胍类似物不同，衍生物 和 对凝血产生更深远的影响；然而，它们对 HUVEC 的细胞毒性也更大，因为 IC 值为 1.0-1.5 mM。总之，将二甲双胍支架化学修饰成具有烷基取代基的磺酰胺会形成具有潜在双向活性的新型衍生物，包括抗高血糖特性和非常理想的抗凝血活性。
