Pleuromutilin derivatives:From antibiotics to antidiabetics

【作者】 徐志斌； 王士亚； 李冲； 刘洋； 董英杰；

【Author】 Zhi-Bin Xu;Shi-Ya Wang;Chong Li;Yang Liu;Ying-Jie Dong;Department of Applied Chemistry and Pharmaceuticals,Beijing Institute of Technology;

【机构】 Department of Applied Chemistry and Pharmaceuticals,Beijing Institute of Technology；

【摘要】 Pleuromutilin is a diterpene with a fused 5-6-8 tricyclic skeleton,first isolated in 1951¹.Its mechanism of action was identified as the selective inhibition of bacterial protein synthesis through interaction with the 50S subunits of prokaryotic ribosomes,and consequently,has rarely exhibited cross-resistance with marketed antibacterial classes².Hundreds of pleuromutilin derivatives have been tested in vitro against Mycobacterium tuberculosis by GlaxoSmithKline and a number of lead compounds with high potency and most promising pharmacokinetics have been identified.But we noted that tiamulin can inhibit both ATPase and drug transport activities of P-glycoprotein in plasma membranes from tumor cells combination with anticancer drug⁴.It suggested that pleuromutilin derivatives might have new application.We designed and synthesized eight novel pleuromutilin derivatives and their bioactivity were screened in vitro through Eli Lilly’s Open Innovation Drug Discovery（OIDD）program.It was very interesting that three analogues stimulate secretion of glucagon-like peptide one（GLP-1）in mouse（mSTC-1）or human（hNCI-H716）cell lines derived from gastrointestinal tissue.GLP-1 secretion was measured using a Lilly proprietary ELISA assay that was specifically designed to detect the appropriate forms of GLP-1 secreted from these cells.The EC₅₀ of one compound is 10.66μM in mSTC-1 cell lines.It may be a good starting point for the development of GLP-1 receptor agonists from pleuromutilin derivatives.更多还原

【Abstract】 Pleuromutilin is a diterpene with a fused 5-6-8 tricyclic skeleton,first isolated in 1951¹.Its mechanism of action was identified as the selective inhibition of bacterial protein synthesis through interaction with the 50S subunits of prokaryotic ribosomes,and consequently,has rarely exhibited cross-resistance with marketed antibacterial classes².Hundreds of pleuromutilin derivatives have been tested in vitro against Mycobacterium tuberculosis by GlaxoSmithKline and a number of lead compounds with high potency and most promising pharmacokinetics have been identified.But we noted that tiamulin can inhibit both ATPase and drug transport activities of P-glycoprotein in plasma membranes from tumor cells combination with anticancer drug⁴.It suggested that pleuromutilin derivatives might have new application.We designed and synthesized eight novel pleuromutilin derivatives and their bioactivity were screened in vitro through Eli Lilly’s Open Innovation Drug Discovery（OIDD）program.It was very interesting that three analogues stimulate secretion of glucagon-like peptide one（GLP-1）in mouse（mSTC-1）or human（hNCI-H716）cell lines derived from gastrointestinal tissue.GLP-1 secretion was measured using a Lilly proprietary ELISA assay that was specifically designed to detect the appropriate forms of GLP-1 secreted from these cells.The EC₅₀ of one compound is 10.66μM in mSTC-1 cell lines.It may be a good starting point for the development of GLP-1 receptor agonists from pleuromutilin derivatives.更多还原