Design, Synthesis And Activity Determination Of New Compounds Based On Louret B Structure

Compound Dragon's blood B,belonging to the dihydrochalcone compounds,was generally considered to be an indicator component for the identification of dragon's blood in content studies and quality determination.As the research progresses,the flavonoids based on Loureirin B fully demonstrated the similar activity of Dragon's blood in pharmacological experimental analysis and clinical trials,which also implied the monomeric dragon hemoglobin B might has the associated activity.In vitro,the dragon hemoglobin B monomer can effectively inhibit the voltage-gated sodium channel and exhibit good analgesic activity in the pain model in mice.For potassium channels,especially Kv1.3 potassium channels,it was considered to be closely related to the autoimmune diseases.After administration of lutein B,the symptoms of autoimmune diseases was effectively alleviated.Also in pain signaling test,the TRP channel superfamily of calcium channels was also very active,and the effect of Dragon's blood B cannot be ignored.Therefore,in order to find new lead compound,based on the structure of the hemoglobin B structure,we consulted the capsaicin structure of the specific activator of TRPV1 channel,the target compound 4-hydroxyN-(2,4,6-trimethyl)oxybenzyl)benzamide was designed and synthesixed.Then,tested its effect on sodium,potassium and calcium ion channels.The preliminary work of this subject(Chapter 2)used the initial starting material 1,3,5-trimethoxybenzene to synthesize 4-hydroxy-N-(2,4,6-trimethyl)by amination reaction,reduction catalysis,dehydration condensation and other means.The oxybenzyl)benzamide precursor compound was further subjected to hydrolysis reaction of an ester bond to obtain the final product,and the structure of the target compound was verified by a NMR and MS.he third part(Chapter 4)mainly used HEK293-T cells as experimental subjects to explore the effect of target compound on potassium channels.We found that the modified target compound was almost Kv1.1,Kv1.2 and Kv1.3 channels.There were no obvious inhibitory effect.After the structural modification of Loureirin B,its selectivity to potassium channels was completely disappeared,which means that its specificity for other channels was improved.The third part(Chapter 4)mainly used HEK293-T cells as experimental subjects to explore the effect of new compounds on potassium channels.It was found that the modified new compounds were almost Kv1.1,Kv1.2 and Kv1.3 channels.There is no obvious inhibitory effect.After the structural modification of Loureirin B,its selectivity to potassium channels is almost completely disappeared,which means that its specificity for other channels is improved.The fourth part of this topic(Chapter 5)focused on the pharmacological effect of target compound on sodium channels.Based on DRG cells,it was determined that target compound could inhibit the maximum peak current of DRG sodium channel current and the maximum activation voltage.It was shifted by about 10 mV in the depolarization direction,indicating that the sodium channel current was more difficult to activate under the action of the target compound.In addition,the inhibitory current of the target compound was consistent with the inhibitory current of tetrodotoxin,indicating that the target compound could inhibit the TTX-S sodium channel.For this reason,the Nav1.7 sodium channel was represented by the TTX-S sodium channel to determine the activity of the target compound.The results showed that the target compound inhibited the Nav1.7 sodium channel current in a concentration-dependent manner,IC50 = 54.026 ± 4.79.This study determined that the modified compound retained selectivity for the sodium ion channel,and the sodium ion channel was closely related to the pain signaling,indicating that the target compound has quite good analgesic activity.The final part(Chapter 6)based on two pain models,measured the analgesic activity of the target compound in the pain model in mice,and found that in the formalin-induced pain model,the target compound was in both the first phase and the second phase.With good analgesic effect,the pain caused by direct stimulation of capsaicin could also be effectively relieved,indicating that the target compound could also exhibit good analgesic activity in the case of activation of calcium channel.In summary,this topic was feasible after analyzing the structure of capsaicin based on the structure of the Loureirin B.The selectivity of the target compound to sodium channel was significantly improved,and the main pharmacological activity was analgesia.This revealed the basis of the structure of the Loureirin B structure in three ion channels,which provided an effective idea for subsequent research..