Synthesis Of Yunaconitine Derivatives And Clinical Effect Observation Of Bulleyaconitine A

Objectives:Part one:The structure of Yunaconitine at C-3,C-8 and C-14 was modified by organic synthesis methods to screen out the compounds with better pharmacological activity and lower toxicity from the obtained series of derivatives for further study.Part two:The application of Bulleyaconitine A in the First Affiliated Hospital of Kunming Medical University was investigated and its clinical efficacy was observed to provide a new idea for clinical research on the treatment of chronic pain.Methods:Part one:A series of derivatives were synthesized by oxidation,reduction,condensation and other chemical reactions.The hydroxyl group at C-3 of Yunaconitine was dehydrated under the action of SOCl2,forming compound 1 which had a double bond between C-2 and C-3.Compound 1 could be reduced to compound 4 by Raney nickel catalysis and H2.Compound 2 and 3 were got under the combined action of NaH,CS2 and MeI,then both of them reacted with AIBN and nBu3SnH to acquire compounds 4-5.Compound 4 was acetylated to form compound 6;the C-8 acetyl ester group and C-14 benzoyl ester group of compound 5 were hydrolyzed simultaneously by NaOH/MeOH to gained compound 7.In addition,the C-3 of Yunaconitine could be attacked by DAST,Biotin,NaH/MeI or DMP to obtain corresponding compounds 8-11,and then intermediate compound 11 could react with H2NOH·HCl/NaOAc,pyrrolidine/NaBH3CN,respectively,to get compounds 12-13.Yunaconitine was also substituted by different groups to form compounds 14-18,and then they were hydrolyzed separately to corresponding compounds 19-23 in the presence of NaOH/MeOH/THF.Moreover,compounds 22-23 reacted with(BOC)2O acylation reagent to form corresponding compounds 24-25.Part two:We collected the medical records of patients who were treated in the inpatient department of the First Affiliated Hospital of Kunming Medical University and used Bulleyaconitine A tablets from January 1st to December 31,2020.The visual analogue scale(VAS)was identified as the observation index of clinical efficacy of Bulleyaconitine A.According to the changes of VAS scores before and after treatment reflecting the changes of pain intensity,we used the VAS weighted value as the evaluation standard to calculate the effective rate of Bulleyaconitine A in the treatment of patients with different degrees of pain.Results:Part one:The structure of Yunaconitine was modified by new synthetic methods,and 23 new Yunaconitine derivatives and 2 reported compounds were obtained.Part two:According to the total VAS weighted value was 56.27±13.69,which indicated that Bulleyaconitine A was effective in the treatment of chronic pain.The effective rate of mild pain was 100.00%,moderate pain was 91.38%,but severe pain was only 41.43%.It followed that Bulleyaconitine A tablets for the treatment of mild and moderate pain had a good effect,but not for severe pain.Conclusions:Part one:We were eager to find out the compounds with better pharmacological activity and lower toxicity would be found in the synthesized series of Yunaconitine derivatives,which could provide supporting materials for the future evaluation of the safety,efficacy of Aconitum compounds and for the studies of their mechanism of action,pharmacokinetics,drug resistance and other aspects.Part two:The VAS score of patients with chronic pain decreased significantly after taking Bulleyaconitine A tablets for one week,which indicated that Bulleyaconitine A was of great help to improve the quality of life of patients,especially suitable for long-term use in patients with opioid drug resistance or gastrointestinal history.In addition,Bulleyaconitine A tablets could also be combined with opioid potent analgesics in the treatment of severe pain,which not only could reduce the dosage and frequency of opioid drugs,but also the dependence and addiction of patients to opioid drugs.