Novel triazine-based pyrimidines suppress glomerular mesangial cells proliferation and matrix protein accumulation through a ROS-dependent mechanism in the diabetic milieu

• Published in: Bioorganic & medicinal chemistry letters 2019-07, Vol.29 (13), p.1580-1585
• Main Authors: Diab El-Harakeh, Mira, Njeim, Rachel, Youssef, Ali, Youssef, Natalie, Eid, Assaad A., Bouhadir, Kamal H.
• Format: Article
• Language: English
• Subjects: Diabetic nephropathy; Novel carbocyclic nucleoside; Reactive oxygen species; Triazine-based Pyrimidines
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2019.04.052

[Display omitted] Diabetic nephropathy (DN) is one of the most serious complications of diabetes worldwide. It is depicted as the leading cause of end-stage renal disease. Oxidative stress plays a key role in hyperglycemia-induced DN. The preparation and characterization of novel mono-, di-, and trisubstituted-s-triazines endowed with uracil and/or thymine are described in this paper. The synthesis of the title compounds was realized through selective nucleophilic substitution reactions of cyanuric chloride with the corresponding hydrazide nucleobases. In this study, we assessed the effects of these derivatives on the progression of diabetic nephropathy. Our results show that trisubstituted-s-triazines endowed with acylhydrazides attenuate high-glucose induced glomerular mesangial cells proliferation and matrix protein accumulation in vitro. Notably, these derivatives also display anti-oxidative properties. This suggests that the novel trisubstituted-s-triazine derivatives provide renal protection through a reactive oxygen species (ROS)-dependent mechanism. Our data provide evidence that these derivatives may serve as potential therapeutic candidates in the treatment of DN.