Design,Synthesis And Evaluation Of Anti-tumor Activity Of "Polyamine-Naphthalamide" Derivatives

Malignant tumors are the main killers that threaten human’s life and health.The main reasons why many cancers cannot be completely cured are easy diffusion,easy transfer and high recurrence rate.Therefore,developing the antitumor drugs with high efficience,selectivity and low toxic and side effects remains one of the maJor challenges in the treatment of cancer at this stage.Polyamines are a class of long-chain aliphatic compounds containing multiple amino or imino groups and are widely found in living organisms.Some studies have shown that fast-growing cells have higher levels polyamines than the normal cells;in addition,polyamines directly or indirectly participate in the process of the cell’s proliferation,differentiation and metabolism.The 1,8-naphthalimide structure is a typical DNA embedding machine and fluorescent dye matrix.In recent years,the role of naphthalimide derivatives in the field of anti-tumor,small molecule fluorescent probes and dyes has been gradually developed,which is one of the hot topics in recent years.Naphtholactam is a kind of benzoindolones,having a wide range of biological activities and it can be used as DNA intercalators and has important prospects in the fields of pharmaceutical development,dyes,and the like.Flavonoids are widely found in the plant kingdom and have antibacterial,anti-inflammatory,anti-tumor,and senile dementia activities.However,due to the structure of flavonoids,their water-solubility is poor,their bioavailability is significantly reduced,and they are not widely used clinically.Recently,our research group found that polyamine-naphtholactam derivatives have good anti-tumor activity.Depending on the principle of pharmacophore synthesizing,this paper took advantage of the polyamine’s good specific target carrying capacity and water-solubility then synthesized a series of compounds which were water-soluble,high bioavailability,anti-tumor activity.I synthesized 20 new compounds that were bifunctional with polyamine-naphtolactam-flavonoids.And through the screening and optimization of chemical reaction conditions,the total yield of the reaction is effectively improved,facilitating the preparation of gram scales.Among them,C1,C6,and C9 are the target compounds of polyamine-naphtolactam-flavonoids" with relatively good activity;on this basis,the preliminary exploration of the structure-activity relationship of C1 has been carried out,enriching the diversity of compounds and facilitating Further study of the "structure-activity-toxicity" relationshipMost naphthalimides have poor solubility.In this paper,a series of potential antitumor drugs have been synthesized by using the polyamines’ water-solubility and targeted carrying capacity,linking the nitrogen-containing heterocyclic olefins with naphthalimides via palladium-carbon coupling reactions,and modifying them with polyamines.The 12 new compounds have strong fluorescence propertiesMTT assay was used to evaluate the in vitro anti-proliferation activity of the compounds.The results showed that some of the compounds not only have good anti-tumor in vitro,but also show strong fluorescence properties.The compounds C1,C6 and C9 showed high inhibition rates at 10 μM for HepG2 and HCT-116 and have the significant cytotoxicity.The compound Y4 showed great anti-tumor activity against triple negative breast cancer and has good fluorescence propertiesIn summary,it is of positive significance to design and synthesize organic small molecules with anti-tumor and potential fluorescent probes for cell localization with the polyamine as the main line.These target compounds may be further studied as compounds for antitumor and precise treatment.