Zajda Agnieszka, Sikora Joanna, Hynninen Mira, Tampio Janne, Huttunen Kristiina M, Markowicz-Piasecka Magdalena
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.
Chem Biol Interact. 2023 Mar 1;373:110381. doi: 10.1016/j.cbi.2023.110381. Epub 2023 Feb 4.
Metformin, the most frequently prescribed medicine for the management of type 2 diabetes, has been shown to reduce cardiovascular events in diabetic patients in pre-clinical and clinical studies. The present work reports the design, synthesis, and biological assessment of the impact of six benzenesulfonamide biguanides on various aspects of hemostasis, cell function, red blood cell integrity (RBC), and their ability to uptake glucose in human umbilical endothelial cells (HUVECs). It was found that all synthesized o- and m-benzenesulfonamides, particularly derivatives with nitro (3) and amino groups (4), are characterized by a good safety profile in HUVECs, which was further confirmed in the cellular integrity studies. The biguanide analogues with methoxy group (1, 2) and an amino substituent (5, 6) significantly increased glucose utilization in HUVECs, similarly to the parent drug. Intriguingly, compounds 1, 3, and 6 favourably influenced some of the coagulation parameters. Furthermore, derivative 3 also slowed the process of fibrin polymerization, indicating more beneficial anti-coagulant properties than metformin. None of the novel metformin analogues interact strongly with the erythrocyte lipid-protein bilayer. Our findings indicate that derivative 3 has highly desirable anti-coagulant properties, and compounds 1 and 6 have potential dual-action activity, including anti-hyperglycaemic properties and anti-coagulant activity. As such, these derivatives can be used as lead molecules for further development of anti-diabetic agents with a beneficial effect on hypercoagulability.
二甲双胍是治疗2型糖尿病最常用的药物，临床前和临床研究表明，它可降低糖尿病患者的心血管事件发生率。本研究报告了六种苯磺酰胺双胍对止血、细胞功能、红细胞完整性（RBC）以及它们在人脐静脉内皮细胞（HUVECs）中摄取葡萄糖能力等多个方面影响的设计、合成及生物学评估。研究发现，所有合成的邻位和间位苯磺酰胺，特别是带有硝基（3）和氨基（4）的衍生物，在HUVECs中具有良好的安全性，这在细胞完整性研究中得到了进一步证实。与母体药物相似，带有甲氧基（1, 2）和氨基取代基（5, 6）的双胍类似物显著提高了HUVECs中的葡萄糖利用率。有趣的是，化合物1、3和6对某些凝血参数有有利影响。此外，衍生物3还减缓了纤维蛋白聚合过程，表明其抗凝血特性比二甲双胍更有益。所有新型二甲双胍类似物均未与红细胞脂质 - 蛋白质双层发生强烈相互作用。我们的研究结果表明，衍生物3具有非常理想的抗凝血特性，化合物1和6具有潜在的双重作用活性，包括抗高血糖特性和抗凝血活性。因此，这些衍生物可作为先导分子，用于进一步开发对高凝性有有益作用的抗糖尿病药物。
