| Objective: Halogenated aromatic rings are active groups commonly found in pharmaceuticals.In the preliminary research work,the research group based on computer-aided drug design technology,through the virtual high-throughput screening,the curcumin compounds have lower binding energy to the MDM2-p53 target.In this paper,based on the active group splicing strategy,a class of curcumin compounds substituted by halogenated aromatic rings was constructed.It is expected that the rationally designed novel curcumin derivatives can enhance the inhibition of MDM2-p53 and improve its pharmacokinetic characteristics in vivo.Method: According to literature research,Curcuma has a wide range of biological activities.We used three common turmeric medicinal herbs such as turmeric,medlar and turmeric as screening objects,and downloaded all the compounds of three kinds of traditional Chinese medicines from the TCMSP database to form a small molecule database.Then,using the tumor protein MDM2-p53 as the target protein,the constructed small molecule database was screened by virtual screening technique,and the curcumin compound had lower binding energy to MDM2-p53 protein.We used curcumin as a lead compound to splicing the common halogenated aromatic ring structure of the existing MDM2-p53 target small molecule inhibitors "Nutlin" series and "MI" series structure,and rationally designed a series of new curcumin.MDM2-p53-like target inhibitor.The binding conformation of the target compound to the receptor protein MDM2-p53 indicates that the curcumin derivative adds a novel force to curcumin.Further,the target compound was subjected to reverse synthesis analysis.The curcumin was used as the raw material,and the optimal synthesis route was determined by wilamson etherification.The synthesis conditions were optimized to obtain the target compound.Results: High-throughput virtual screening showed that curcuminoids had lower binding energy to MDM2-p53,which was used as a lead compound to splicing the halogenated aromatics shared by the existing "Nutlin" series and "MI" series MDM2-p53 inhibitors.The ring group gives the compound Ta,Tb.The minimum binding energy of the compound Ta,Tb and the target protein MDM2-p53 was significantly higher than that of curcumin.By analyzing its force,the target compounds Ta,Tb and MDM2-p53 protein residues increased the intermolecular interaction force.Through reverse synthesis analysis,the target compound Ta,Tb was obtained by using curcumin as the raw material,acetone as the solvent,potassium carbonate and potassium iodide as the catalyst,and reacting at 60 ° C for 12 h.During the post-treatment process,Ta and Tb were found to be chiral isomerized,and it was difficult to separate and purify.It was difficult to obtain a single conformation compound,and the structure of Ta and Tb was unstable,and the nuclear magnetic resonance spectrum was complicated.Then the modified mother nucleus is replaced by a structurally similar melatonin,which is modified as a lead compound to synthesize new compounds e1,e2,e3,e4.Conclusion:(1)Curcumin and its derivatives are one of the main components of the antitumor activity of curcuma.(2)The halogen on the benzene ring in the MDM2-p53 target protein inhibitor has a significant effect on its activity.The antitumor activity can be significantly enhanced when the halogen-containing benzene ring is attached to the curcumin and melatonin core.(3)There is chiral isomerization in the synthesis of curcumin derivatives,and structural instability is difficult to separate to obtain a single configuration compound.(4)The melatonin derivative is structurally stable and easily isolated to obtain a single conformational compound. |
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