Semi-Synthesis And Biological Evaluation Of A Platensimycin Click Chemistry Library And Its Polyethylene Glycol Derivatives

Purpose.Natural products are important sources of drugs,and play a prominent role in the discovery of many small molecule drugs.Platensimycin（PTM）and Platencin（PTN）are potential antibiotic drugs obtained by high-throughput screening of microbial fermentation extracts,which have strong inhibitory effect against most gram-positive bacteria.PTM not only is a selective inhibitor of the FASII enzyme Fab F,but also has been found to inhibit human fatty acid synthase against metabolic diseases.However,the poor pharmacokinetic properties of PTM and platencin hampered their clinical development.In this Thesis,the main purpose of this work is to develop PTM analogues with improved activity and improved pharmacokinetic properties.Methods and results（1）.Semi-synthesis and biological evaluation of a platensimycin click chemistry library.We first synthesized 6-azidyl PTM derivative（2a）by the nucleophilic substitution reaction between sodium azide and platensimycin oxide（PTMO）.Using 2a and 70compounds bearing a terminal alkyne as substrates,the platensimycin click chemistry library with 70-members was synthesized in high yields by optimizing the conditions of click chemistry reactions.We next evaluated the antibacterial activity and the anti-proliferative activity of the prepared library.The antibacterial activities of all the synthesized compounds were lower than PTM against the tested Staphylococcus aureus strains using the paper-disc method.The antibacterial activities of the compounds 4,5,20,41,42 were higher than PTM against the tested M.smegmatis strains.The antibacterial activities of the compounds 4 were higher than PTM（MIC=16μg/m L）.In contrast,a serious of PTM derivatives from this library,including 5,6,7,13,14,15,19,34,42,44,54,60,65,67 and 70 showed inhibitory activity from 32.3%to 38.2%against A549 cells at 25μg/m L.We therefore resynthesized several of them,including 7,13,14,15,19,34,42 and 44,and tested their IC₅₀against A549 cells.The compounds 7,15,19showed certain inhibitory activity against A549 cells(IC₅₀=28.8μM,IC₅₀=56.65μM,IC₅₀=43.4μM).Methods and results（2）.Semi-synthesis and biological evaluation of platensimycin polyethylene glycol derivatives.We previously showed that 7-thioether PTM derivatives could be obtained by sulfa-Michael addition reaction.Therefore,compounds 3a and 3b were similarly prepared by the reaction of PTM and mercapto-containing polyethylene glycols with molecular weights of 500 and 2000,respectively.We also found that 3a could self-assemble in solvent to form homogeneous nanoparticles.In vitro antibacterial assay showed that the MICs of 3a and3b against S.aureus were more than 256μg/m L,indicating that both of them may not be able to cross cell membranes effectively.In vitro and serum stability assay revealed that 3a had good stability and could release PTM slowly throughβ-elimination reaction.This suggests that these PTM polyethylene glycol derivatives may improve the pharmacokinetic properties of PTM in vivo.Conclusion.In this work,we established a rapid method to construct PTM derivative library.In comparison to PTM,the anti-Staphylococcus activity of these PTM derivatives are attenuated,the antibacterial activities of some compounds were higher than PTM against the tested M.smegmatis strains,while several of them exhibited improved anti-proliferation activity than PTM.The synthesis and evaluation of PTM polyethylene glycol derivatives may facilitate our future development of alternative PTM conjugates.Therefore,our study not only provides two different types of PTM derivatives,but also showed that late-stage functionalization of natural products is an effective method for drug lead development.