Synthesis And Antitumor Activities Studies Of Simplified Analogs Based On Nitidine Chloride Skeleton

Objective:Nitidine Chloride（NC）is a kind of benzophenidine alkaloid isolated from Zanthoxylum nitidum（Roxb.）Dc.,and studies have shown that NC has anti-inflammatory,anti-bacterial,anti-viral,anti-malaria and anti-tumor activitieswith and other biological activities.Among them,the study of NC’s anti-tumor activity is more remarkable.It not only inhibits the growth of various tumor cells such as lung cancer,breast cancer,colon cancer and liver cancer in vitro,but also has obvious inhibitory effect on the growth of mouse S180 sarcoma and H22 liver cancer xenograft in vivo.However,due to its poor water solubility,low bioavailability and cytotoxicity,the further clinical application is limited.Therefore,it is imperative to design and synthesize a series of diamidine derivatives with improved water solubility and high efficiency and low toxicity using nitidine chloride as the lead compound.Methods:To design and synthesize a series of simplified two-sided acinar derivatives by reducinguble aromatic ring,introducing polar groups and active splicing.The main contents are as follows:Firstly,using substituted benzoyl chlorid as starting materials,the simplified biphenylaline phenanthridone skeleton is obtained by acylation,palladium-catalyzed ring closing and deprotection group reaction.Secondly,on the basis of pyridone skeleton,combined with the nucleophilic substitution reaction,active fragments such as thicaptetrazole,sulfamide,thiurerea and thiazole are introduced into the skeleton via different lengths of the bridge chain,and four types of simplified two-sided pinine derivatives are derived;Finally,the CCK8 method is used to screen the target compounds for antitumor activity in vitro,which lay a foundation for further pharmacological research.Results:In this study,a total of 76 simplified skeleton analogues of diamidinechloridearesynthesized.Including diamidroidine-tetrazoliothioether heterozygotes（8a-8t and 9a-9t）,diamidroidine-sulfonamide heterozygotes（15a-15o and 16a-16o）,diamidroidine-thiourea heterozygotes（18a-18e）,diamidroidine-thiazole heterozygotes（20）,and their structures are determined by ¹H-NMR,¹³C-NMR,HR-MS and single crystal X-ray diffraction.The results of pharmacological experiments show that the target compounds have some antitumor effects,among which compounds 8f、15h、15n and 20 show significant inhibitory activity against Hepg2、H460 and He La cells,and the inhibition rates are more than 50%at the concentration of 40μmol/L.It is worth mentioning that compounds 15h,15n and 16h had inhibition rates of82.39%,86.62%and 88.98%on H460 cells,respectively,which are not only superior to the positive control 5-fluorouracil（45.08%）,but also equivalent to its parent nuclear structure diamidine chloride（86.68%）,and less toxic than diamidine chloride.Therefore,these compounds have the potential to be developed as lead anti-tumor compounds with high efficiency and low toxicity.Conclusion:（1）In this study,a method for the synthesis of a new simplified skeleton analogue of nitidine chloride is established,which has the characteristics of good universality,high efficiency and economy.None of the synthesized compounds have been reported in the literature,which further enriches the library of alkaloids derivatives.（2）It is found that some of the simplified skeleton analogs of nitidine chloride have significant anti-tumor activity,which has academic reference significance and inspiration for the subsequent exploration of structure-activity relationship and pharmacological mechanism.