The Synthesis Of α-mangostin Derivatives And Their Inhibitory Activities Towards Phosphodiesterase 4

ObjectiveNumerous researches had shown that PDE4 inhibitors had significant anti-inflammatory effects in vivo and in vitro.But their serious side efforts of nausea and vomiting limit their further application in clinic.So,seeking for the novel PDE4 inhibitors drug is eagerly.Recent studies revealed thatα-mangostin had PDE4 inhibitory activities(IC₅₀≈1μM).However,its typical xanthone class structure characteristics,lead to strong lipotropy,with lower water solubility and low oral bioavailability.In order to improve its physical and chemical properities and enhance its activity towards PDE4,we designed and synthesized a series ofα-mangostin derivaties,and expected to provide the basis of subsequent studies of PDE4 drugs.MethodsAccording to its structural characteristics,five different series of derivatives were designed and synthesized mainly in C-3 and C-6 positions,including:hydroxyl oxime acid series,a series of small molecules of nitrogen,acetylene series,a series of closed loop series and coupled natural products by alkylation reaction.Their chemical structures were determined by analysis of theirnuclear magnetic resonance（NMR）,MS data.The bioassay in vitro towards PDE4 was preformed via[³H]tag liquid scintillation counting method.ResultsForty-four compounds were synthesized in this thesis,including ten intermediates and thirty-four target materials,in which containing twenty-five new compounds.The results of pharmacological tests showed that compounds 2、5、7、10、14、22、25、28、29、31、34、36、37、38、40、44 exhibited good inhibitory effect at the concentration of 10μM,and the inhibition rate could reached more than 50%.At 1μM concentration,the inhibition rate of compound 34 and 38 reached 91.53%and 81.04%,respectively,which was more than that ofα-mangostin（52.84%）.At 0.1μM concentration,compound 34 inhibition rate reached 72.96%,which is better than that of control(the first generation of PDE4inhibitors-Rolipram（0.59μM,50%）.The structure-activity relationship regulars were as follows:（1）The structure-activity relationship showed that the C-3,C-6 phenolic hydroxyl group ofα-mangostin played an important role in its inhibitory activities to PDE4.When the two positions of phenolic hydroxyls were replaced,the activities of most compounds were decreased.（2）When C-2 and C-3 formed a pyran ring,activities of this series were enhanced（3）When C-2 and C-3 formed a pyran ring,and substituted a alkyl chain with carboxyl,pyrone in the C-6,the inhibitory activities were more than that of the active pharmaceutical ingredients.Compared with compounds of mother nucleus unchanged,the activities of this series were enhanced.（4）When the compound of C-4 position was substituted,the activity was better than API.Conclusion25 new derivatives were synthesized in this thesis.We designed and synthesized a series ofα-mangostin derivaties,and studied all compounds inhibitory activities to PDE4.Compound 34:C-2 and C-3 formed a pyran ring,and substituted a alkyl chain with seven carbon carboxyl.The activity of this derivative was the most potent,more than 50 times than that of the initial compound,and it would be taken to the further study in vivo and in vitro.