Design, Synthesis and Pharmacological Evaluation of Naphthofuran Derivatives as Potent SIRT1 Activators.

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.

TLR-2-mediated metabolic reprogramming participates in polyene phosphatidylcholine-mediated inhibition of M1 macrophage polarization.

This study aimed to investigate whether the classic hepatoprotective drug polyene phosphatidylcholine (PPC) regulates macrophage polarization and explores the potential role of TLR-2 in this process. In RAW264.7 macrophages and murine bone marrow-derived macrophages (BMDMs) stimulated by lipopolysaccharide (LPS), PPC significantly inhibited the production of IL-6, TNF-α, and the mRNA expression of M1-type macrophage markers. Consistently, PPC reduced the mRNA expression of several key enzymes in the pathways of glycolysis and lipid synthesis while increasing the expression of key enzymes associated with lipid oxidation. Moreover, blocking the glycolytic pathway using 2-deoxy-D-glucose (2-DG) significantly enhanced the anti-inflammatory effect of PPC. However, inhibition of lipid oxidation using GW9662 (an inhibitor of PPAR-γ) and GW6471 (an inhibitor of PPAR-α) abolished the anti-inflammatory effect of PPC. Interestingly, TLR-2 expression in macrophages was significantly downregulated after exposure to PPC. Moreover, pre-activation of TLR-2 hampered the anti-inflammatory effect of PPC. In addition, PPC did not inhibit the secretion of IL-6 and TNF-α in TLR-2-/- BMDMs that were activated by LPS. This was consistent with the increased expression of M1 markers and glycolytic and lipid synthesis enzymes but decreased lipid oxidation-related enzymes. These results showed that PPC inhibits the differentiation of M1-type macrophages, which was most likely related to TLR-2-mediated metabolic reprogramming.