Synthesis And Biological Activity Of Butenolide Derivatives

Butenolide derivatives have a wide range of pharmacological activities.The main structure of such compounds is a butyrolactone ring?furanone ring?,which is considered to be one of the pharmacophores of biologically active substances.They have played an important role in drug discovery and development of pharmacologically active parts design.Therefore,in this paper,a series of new butenolide derivatives containing 2,5?H?furanone ring were synthesized and named as BL1-BL10,which were based on derivatization of the butyrolactone ring.Then,the synthesized compounds were evaluated for biological activity in vitro.The main research contents of this thesis are as follows:?1?Synthesis of Butyrolactones:Using p-hydroxybenzaldehyde and hydantoin as original materials,piperidine as a catalyst,4-hydroxyphenylpyruvic acid was obtained through Knoevenagel condensation,hydrolysis reaction.Then,4-hydroxyphenylpyruvic acid was methylated under trimethylchlorosilane?TMCS?as a catalyst to obtain methyl 4-hydroxy-phenylpyruvate?the first type of intermediates?.Using p-hydroxybenzaldehyde as original materials,let it be alkylated with1-bromo-3-methyl-2-butene,then benzaldehyde derivant was obtained through2,3-Dichloro-5,6-dicyano-1,4-benzoquinone?DDQ?dehydrogenation,benzyl or tetrahydropyran?THP?protection reaction.Using phenol,glyoxylic acid,benzyl bromide,and methyl iodide as original materials,acetophenone ester derivatives were obtained through alkylation,esterification,substitution,and oxidation reaction;Using4-hydroxyphenethyl alcohol,1-bromo-3-methyl-2-butene,and benzyl bromide as original materials,phenyl alcohol or ketone derivatives?the second type of intermediates?were obtained through substitution and oxidation reaction.Finally,the first and second types of intermediates were catalyzed by1,8-diazabicycloundec-7-ene?DBU?via aldol condensation to obtain the target compounds BL1-BL10.Structure of those compounds were characterized validated by¹H NMR,¹³C NMR and high-resolution mass spectrometry.?2?Evaluation of biological activity of butyrolactone compounds:The CPE method was used to evaluate the antiviral activity of the 10 synthesized compounds at drug concentration of 30?M.The activity screening results showed that BL5 and BL10 had better inhibitory activity for H1N1 influenza virus than the positive control of ribavirin?IC50=23.3?M?,and the IC50 of BL5 and BL10 were 19?M and 23.6?M,respectively.But the 10 synthesized compounds had no inhibitory activity against EV71 enterovirus and HSV-1 and HSV-2 herpes viruses.At drug concentration of 10?M,the compounds BL5,BL8 and BL9 had good PTP1B inhibitory activity with the inhibition rates were 70.1%,53.88%and 64.2%,respectively.Based on the preliminary screening results,an insulin resistance model was established by using high glucose and high insulin to induce HepG2 cells,and the compounds were tested for glucose uptake after insulin resistance in HepG2 cells.The results showed that BL5 and BL8 had a significant effect on improving insulin resistance in HepG2 cells,while BL9 does not produce a hypoglycemic effect due to its toxic effect on islet cells.?3?Chiral separation and activity evaluation of preferred compounds:The compounds BL5 and BL8 were separated by chiral separation to obtained two pairs of enantiomers,then measured its inhibitory acitivity and hypoglycemic activity on PTP1B.The results showed that there was no significant difference in the activity of the enantiomers and racemates,which indicated that the chiral center had no effect on the improvement of insulin resistance in HepG2 cells.