Study On The Inclusion Interaction Between Cucurbit[7]uril And Adefovir Mono-L-amino Acid Ester And Monocholate Derivatives

Objective:The purpose of this thesis is to improve the release effect and physical and chemical properties of liver-targeted adefovir mono-L-amino acid ester and monocholate synthesized in the laboratory,and play an active role in drug delivery and drug release according to the cucurbit[7]uril（Q[7],CB[7]）as a drug carrier.According to the research report on improving drug solubility,stability and reducing drug side effects,adefovir mono-L-amino acid ester and monocholate derivatives were included with Q[7]by host-guest inclusion principle.In order to obtain adefovir mono-L-amino acid ester and monocholate with high stability and reasonable release,monocholate derivatives and Q[7]host-guest compound.To provide research basis for the development of new anti-hepatitis B virus drugs.Methods:（1）Glycoluril was prepared by condensation of Glyoxal and urea under acidic condition,and then mixed cucurbit[n]uril containing many kinds of glycoluril polymers was obtained by dehydration condensation of glycolide and paraformaldehyde at 1:2 molar amount at high temperature and concentrated acid conditions.Then the high purity Q[7]was obtained by column chromatography.A series of adefovir mono-L-amino acid ester and monocholate compounds were dissolved in methanol and their inclusion with Q[7]was detected by UV.（2）The solubilization effect of Q[7]on adefovir mono-L-amino acid ester and monocholate series compounds was detected by solubility method.（3）In order to solve the problem of poor solubility of adefovir mono-L-amino acid ester and monocholate in water,adefovir mono-L-amino acid ester and monocholate oxalate were synthesized.（4）Adefovir mono-L-amino acid ester and monocholate oxalate were dissolved in water,and then the inclusion of adefovir mono-L-amino acid ester and monocholate oxalate with the host and guest of Q[7]was detected by ¹H NMR,IR,UV and ITC,mass spectrometry.（5）A host-guest compound of adefovir mono-L-amino acid ester and monocholate oxalate was prepared with Q[7].The hygroscopic stability of the inclusion complex at room temperature and pressure was studied,and its cumulative release in artificial intestinal juice（p H=6.8）and artificial gastric juice（p H=1.2）was studied by isothermal oscillation method.Results:（1）Q[7]was obtained from the separation and purification of a variety of glycoluril polymers,and the yield of separation and purification was 12.3%.The structure was identified by ¹H NMR and Quadrupole-Time of Flight（Q-TOF）.Adefovir mono-L-amino acid ester and monocholate series compounds have no obvious effect on Q[7]in the case of methanol dissolution.（2）Under the condition of pure water as solvent,Q[7]has different solubilization effects on adefovir mono-L-amino acid ester and monocholate series compounds,among which the solubilization effect on compound 5p is the strongest,which is 5.9 times than that of the original compound.（3）Six adefovir mono-L-amino acid ester and monocholate oxalate were synthesized with a yield of 72.8%～85.6%in step of salt formation reaction.The structures were characterized by ¹H NMR,¹³C NMR and Q-TOF,and the structures of obtained compounds were consistent with the target ones.（4）All six compounds will form host-guest compounds with Q[7].Since guest compounds（5c’,5i’,5j’,5l’,5o’,5p’）have more binding sites,both ¹H NMR and UV detection methods will show the action ratio of the host:guest=3:1～4:1,in the titration process.When the host-guest compounds of compounds 5c’,5i’,5j’,5l’,5o’and5p’were detected by mass spectrometry,the host-guest interaction ratio was 1:1.This result shows that compounds 5c,5i,5j,5l,5o,5p can successfully react with Q[7]after being made into salt,but the dry host-guest compound only has the action ratio of 1:1.In addition,the isothermal titration calorimetry（ITC）results of compound 5c’and Q[7]also showed that the host-guest ratio was 1:1.The results show that the host-guest compound of compounds 5c,5i,5j,5l,5o,5p can successfully form an inclusion complex with Q[7],but the dry host-guest compound only has the action ratio of 1:1.（5）The results of moisture absorption stability show that the host-guest compounds of the six compounds with Q[7]have stronger moisture absorption stability than free compounds.The results of cumulative release in vitro showed that the intervention of Q[7]could reduce the cumulative release of guest compounds except 5o’in artificial gastric juice,indicating that Q[7]had a sustained release effect on compounds 5c’,5i’,5j’,5l’and 5p’in artificial gastric juice.The cumulative release of host-guest compounds of Q[7]with compounds 5c’,5i’,5j’,5l’,5o’and 5p’in artificial intestinal fluid was higher than that of single guest,which indicated that Q[7]could promote the release of compounds 5c’,5i’,5j’,5l’,5o’,5p’in artificial intestinal fluid.Conclusions:In the process of titration,UV and ¹H NMR showed that with the increase of the ratio of Q[7],multiple interaction modes of host and guest coexisted in the system,and there was even an inclusion complex with four Q[7].The Q-TOF and ITC results show that the 1:1 inclusion mode is a stable mode.In artificial gastric juice,Q[7]can control the release of adefovir mono-L-amino acid ester and monocholate oxalate series compounds except 5o’,and Q[7]can promote the release of adefovir mono-L-amino acid ester and monocholate series compounds in artificial intestinal juice.The solid inclusion compound formed by 5c’,5i’,5j’,5l’,5o’,5p’and Q[7]is still white solid after 90 days at room temperature and humidity,indicating that the hygroscopic stability of the host-guest compound was higher than that of the free guest.