Design Synthesis And Anticancer Activity Of New Artemisinin-Nitrogen Mustard Hybrid And Small Molecule

Alkylating agents play an important role in the clinical application of chemotherapeutic drugs.Among them,nitrogen mustard has the most prominent cross-linking performance.It binds to DNA and eventually causes cell death to exert its biological activity.At the molecular level,the aziridinium ions produced by nitrogen mustard are highly reactive to the DNA of tumor cells and have excellent therapeutic significance.This paper optimizes and improves the nitrogen mustard in two ways:1.The hybrid of the nitrogen mustard and the natural product artemisinin;2.The combination of the nitrogen mustard and the nitrogen-containing groups.1.Artemisinin,as an important parent structure for drug design,has a variety of biological activities.In recent years,the development of anticancer drugs using artemisinin as a parent has attracted much attention,and mass of new chemical entities have been obtained;natural products are combined with other pharmacophores are an important means of drug design.According to the idea,we combine artemisinin with nitrogen mustard in order to improve the toxicity of nitrogen mustard.In this paper,24 artemisinin nitrogen mustard hybrids have been synthesized,and their cytotoxic effects on HCT-116,A549,CCRF-CEM,HL-60,K562,SH-SY5,U118-MG have been tested by MTT experiments.The results showed that the anti-tumor activity of most hybrids was enhanced,the most hybrids were less than 10 μM,and the best was 0.555 μM.Among all the compounds,the hybrids 12a and 121 showed a relatively broad-spectrum inhibitory activity,the activity of 12a against CCRF-CEM was 0.895 μM,and 121 showed excellent activity against CCRF-CEM,HL-60,K562 as well as,IC50 is 0.602 μM,1.023μM,2.067μM,and 12a,121 showed excellent selectivity to normal liver cells L-02,in view of the broad spectrum,high efficiency and excellent selectivity of 121,it was selected to explore the possible mechanism of inducing apoptosis of CCRF-CEM.The research results show that significant morphological changes of CCRF-CEM cells can be observed through 121 treatment.Hoechst 33258 staining study found that 121 can induce the formation of visible,densely stained and dense particle fluorescence in the cell nucleus or cytoplasm,and cell proliferation is inhibited.AnnexinV-FITC/PI double staining method showed that green and red fluorescence increased significantly,and cell proliferation was inhibited.In addition,CCRF-CEM cells showed strong green fluorescence through mitochondrial membrane potential staining,which can be inferred that 121 induced apoptosis by changing the depolarization of the mitochondrial membrane.Above all,the excellent activity of the compound 121 and its mechanism research indicate that compound 121 has the value of further research.2.Nitrogen-containing groups are widely used in the field of drug synthesis,they are a class of highly drug-forming compounds.Introducing nitrogen-containing groups into the compound can effectively improve the pharmacokinetic properties and biological activity of the compound with fewer side effects.Studies have shown that diarylurea can reduce the activity of nitrogen mustard,thereby forming relatively stable derivatives and improving bioavailability.Based on it,we have designed and developed small molecule nitrogen mustard compounds containing benzylurea and semicarbazide for development Promising candidate drug molecules.Currently,11 compounds have been designed and synthesized.MTT experimental results show that 17c has a strong inhibitory effect on CCRF-CEM,IC50 value is 0.561 μM,and other compounds are being tested for activity.