Design,Synthesis And Hypoglycemic Activity Of Cytisine Derivatives

Cytisine(Fig.1)is an alkaloid monomer extracted from the seeds of leguminous acacia.It has a wide range of biological activities.Since cytisine had been used in clinic for decades,its safety profile had been widely recognized.In an earlier hypoglycemic high throughput screening of the Chinese natural product compound library,the activity of increasing glucose consumption of cytisine was found for the very first time.In view of its unique three-ring bridge chemical scaffold,cytisine was taken as the lead compound,and the hypoglycemic activity of its kind was studied.Glucose consumption(mmol/L)DMSO 4.14 +0.5 Cytisine(25 ? mol/4.81 ± 0.25 Met(5 mmol/L)8.18 ± 0.25Fig.l The structure and hypoglycemic activity of cytisineDirected by hypoglycemic activity,systematic modification and optimization was carried out focusing on the 12N-substitution fragments,and totally 56 cytisine derivatives were synthesized,then the effect on the glucose consumption in the muscle L6 cells was evaluated and summarized as follows:1)When an alkyl group was introduced to 12N,the growth of the carbon chain might contribute to an increased activity.2)When different benzyl substituents,including electron withdrawing group,electron-donating group and halogen group were introduced to 12N,the introductions of p-CF3(Jqh-1-3)and p-I(Jqh-1-6)might be beneficial to the activity.3)Most of the introduction of sulfonyl or formyl groups on the 12N atom might lead to an increase of activity in varying degrees.4)The introduction of appropriate aminoformyl or aminothioformyl group on the 12N atom might be helpful for the activity,such as Jqh-8-8.Further study identified that the the representative compounds Jqh-1-3,Jqh-1-6 and Jqh-8-8 could enhance the glucose consumption effect in L6 cells significantly in a concentration-dependent manner.The glucose consumption effects of the key compounds were also wintnessed in HepG2 hepatocytes and 3T3 adipocytes respectively.The primary mechanism study indicated that:compounds Jqh-1-3 and Jqh-8-8 could up-regulate the expression of glucose transporter protein Glut4 and the level of AMPK phosphorylation in a dose-dependent manner,suggesting that these compounds may increase the cellular glucose consumption by up-regulating Glut4 expression and activating AMPK kinase.In the following in vivo pharmacokinetic study,Jqh-1-3 and Jqh-8-8 gave the Cmax.values of 2.81 ?mol L-1 and 0.13 ?mol·L-1,and AUC values of 2.50 ?mol·L-1 h and 0.78?mol·L-1h respectively,indicating that Jqh-1-3 had better drugablility and was thus more promising for fturther study.The poorer pharmacokinetic profiles of Jqh-8-8 might result from the hydrolytic amide bond.Totally 56 compounds(in which 48 were novel)were synthesized,and their structures were confirmed by 1H NMR?13C NMR and HRMS.The effect of various 12N-substitutions to the glucose consumption was systematically summarized.Among them,Jqh-1-3 exhibited ideal hypoglycemic activities and an excellent pharmacokinetic profile.All these results above indicate that tricyclic cytisinic derivatives were a class of novel and promising hypoglycemic compounds.This study provided useful scientific data for further structural modification and optimization of these compounds.Intensive mechanism of related candidates is in progress.Part of the work was published in Acta Pharmaceutica Sinica(2018).