Design, synthesis and biological evaluation of a hybrid compound of berberine and magnolol for improvement of glucose and lipid metabolism

摘要

The discovery and structural optimization of lead compounds is the main task in the research and development of new drugs. In order to search for new compounds with greater activities and lower toxicity, the synthesis of two or more basic structures of drugs bonded together has been designed on the basis of combination principles. Here, a hybrid compound consisting of berberine (Ber) and magnolol (Mag) was synthesized and its biological activities were evaluated. We named the hybrid compound Huanghousu (HHS), and its size and structure were confirmed by spectroscopy ( ~(1) H NMR, ~(13) C NMR and HRMS spectra). The LD _(50) of HHS was determined in NIH mice by intraperitoneal injection according to the modified Karber's method. Treatment of transgenic aP2-SREBP-1c mice with HHS markedly reduced blood triglycerides (TG) and improved sugar tolerance. In addition, we also evaluated the effects of berberine, magnolol and HHS on the proliferation and differentiation of 3T3-L1 preadipocytes and investigated the underlying mechanism. The adipocyte differentiation-related genes PPARγ and C/EBPα were tested using a real-time quantitative polymerase chain reaction (real-time PCR). In addition, FAS, UCP2 and adiponectin mRNA, which are related to adipocyte adipogenesis, were also measured in mature 3T3-L1 adipocytes induced by differentiation medium. The efficacy of HHS in preventing obesity was somewhat greater than that of magnolol or berberine. Taken together, these results indicated that HHS was effective in improving disorders of glucose and lipid metabolism in vivo and regulating lipid metabolism-related gene expression in vitro .