Abstract
Diabetic nephropathy (DN) is one of the most important medical complications in diabetic patients, which is an essential cause of end-stage renal disease in diabetic patients and still lacks effective medicines. Silent information regulator 1 (SIRT1) is closely related to the occurrence and development of DN. Activation of SIRT1 could significantly improve the symptoms of DN, while the activities of SIRT1 activators need to be further improved. Based on the crystal structure of SIRT1, structure and ligand-based approaches were carried out, and a lead compound 4,456–0661 (renamed as M1) was identified. Moreover, seven M1 analogues (6a-6g) were designed using a structure-based drug design strategy followed by bioactivity evaluation with SRTR2104 used as positive drugs. Among the target molecules, compounds M1, 6b, and 6d were proved to be potent SIRT1 activators, the activities of which are comparable to SRT2104. More importantly, compounds M1, 6b, and 6d could resist high glucose-induced apoptosis of HK-2 cells by activating SIRT1 and deacetylation of p53. Apart from the beneficial effect on apoptosis of DN, these compounds also alleviated high glucose stimulating inflammation response in HK-2 cells through SIRT1/NF-κB (p65) pathway. Consequently, M1, 6b, and 6d could be promising drug candidates for SIRT1 related diseases.
Highlights
As per international diabetes federation data, 463 million adults were living with diabetes worldwide in 2019, and this number would double by the year 2045
The binding site is located in the N-terminal domain of Silent information regulator 1 (SIRT1), which aims for the specific allosteric activation mechanism of SIRT1 activator
Melting points of individual compounds were determined on a model YRT-3 apparatus and uncorrected. 1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were performed on a JEOL (400 MHz)
Summary
As per international diabetes federation data, 463 million adults were living with diabetes worldwide in 2019, and this number would double by the year 2045. The current number of diabetic patients in China is as high as 114 million, still ranking first in the world (Saeedi et al, 2019). Diabetic nephropathy (DN) is one of the most critical medical complications in diabetic patients. It is one of the most important factors that cause end-stage renal disease (ESRD) in diabetic patients. Its higher morbidity and mortality have significantly increased the economic burden on patients with diabetes and society (Hsu et al, 2009; Flyvbjerg, 2017). To date, there is still a lack of effective drugs and approaches to halt the progression of DN
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