Design,Synthesis Of α-Mangostin Derivatives And Evaluation Of Their Inhibitory Activities Against Phosphodiesterase 4

Phosphodiesterase 4(PDE4)is a specific enzyme that catalyzes the hydrolysis of cAMP.Its inhibitors are important therapeutic drugs for various inflammatory and immune diseases.However,the side effects such as nausea and vomiting are common in this type of medicine and seriously affect the clinical application of them.The research and development of novel PDE4 inhibitors with high efficiency and low toxicity are urgently needed.Mangosteen’s peel is a traditional medicine used to treat abdominal pain,chronic ulcer and other diseases in Southeast Asian countries.Its main pharmacological component,α-Mangostin,has shown anti-inflammatory,antioxidation,anti-tumor,antibacterial and neuroprotective activities in various studies.In the early stage of our study,it was found α-Mangostin is a PDE4 inhibitor,which inhibitory activity can be improved by structural modification,but the structure-activity relationship needs to be clarified.In order to obtain a novel type of PDE4 inhibitor with high efficiency and low toxicity,and also to provide the lead compound for the subsequent development of PDE4 inhibitor drugs,the design of new derivatives of αMangostin based on the information provided by the co-crystal structure of PDE4 protein with α-Mangostin’s derivatives was carried out.These α-Mangostin’s derivatives were prepared by alkylation,hydrolysis,acylation and other methods and their activities of PDE4 inhibition in vitro was evaluated by enzymatic reaction of tritium substituted substrate.The structure-activity relationship of PDE4 inhibition was comprehensively analyzed and clarified.In this thesis,82 α-Mangostin derivatives have been successfully synthesized,including 75 new compounds.Among them testing the PDE4 inhibitory activity,31 derivatives show stronger PDE4 inhibitory activity than α-Mangostin;The IC50 values of 18 derivatives(4b-4d,4f,4g,5d,19,31-33,45-51,53)are less than 100 nM and 9(4b,4f,19,33,46-48,51,53)of them less than 50 nM.Two most potent compounds are 4f and 51 with the IC50 values of 16 nM and 11 nM respectively,which are 81 and 119 fold than the parent compound,α-Mangostin.At the same time,the structureactivity relationships show that:(1)after intramolecular cyclization between the C-2 and C-3 position,the substitution of alkylcarboxylic acid group(C-6),crotonic acid group(C-1)or α-ester group(C-1)can improve the inhibitory activity against PDE4.(2)If the alkyl carboxylic acid group at the C-6 position of the α-Mangostin ring-closed derivative is the only one substituted group,then when the number of alkyl chain on the substituent is 6-7 carbons,the activity is stronger.(3)If the crotonic acid group is introduced at the C-1 position of the α-Mangostin ring-closed derivative,the activity is stronger when the benzyl group is introduced at the C-6 position at the same time.(4)Once the terminal carboxyl group of active derivatives are esterified or replaced by Br group,their inhibitory activities will greatly be decreased.The results obtained in this thesis are expected to promote the pharmacodynamic test and further structural optimization of active α-Mangostin derivatives,and to provide lead compounds for the research and development of novel PDE4 inhibitors.