Design And Synthesis Of Derivatives Of Anti-Hepatocarcinoma Drug Tetrazanbigen

Liver cancer is a chronic non-communicable disease,and the number of liver cancers in the world is increasing year by year.The existing anti-hepatocarcinoma drugs also affect the physiological functions of normal cells when killing liver cancer cells,and cause bone marrow suppression,hepatotoxicity,nephrotoxicity and cardiotoxic side effects,and the problem of drug resistance becomes the main reason for limiting the clinical application of anti-hepatocarcinoma drugs.Deazepide is a new non-cytotoxic anti-liver cancer drug with an innovative configuration and has been invented by the state in 2001.Our previous in vitro study showed that TNBG has good anti-hepatocarcinoma activity against solid hepatoma cells;in vivo experiments confirmed that TNBG can significantly prolong the survival of tumor-bearing mice and tumor-bearing rabbits,although TNBG in vitro and in vivo pharmacodynamic experiments show TNBG has a good development prospect.However,TNBG has poor water solubility and is not easy to be prepared into oral or intravenous preparations,which reduces the exposure of the compound and affects the exertion of the drug,which severely limits its drug-forming properties.In this paper,a lipid-based anti-hepatocarcinoma compound TNBG was used as a lead compound to introduce a hydrophilic group on the TNBG A ring,and a structure-activity relationship study was carried out.It is expected that a highly effective,low-toxic,and well-established anti-hepatocarcinoma candidate molecule can be obtained.The research work of this paper is summarized as follows:1.Using p-methoxyphenethylamine as starting material,synthesizing p-methoxy ATIQ by acylation,alkylation,cyclization,reduction and deuteration;using o-phenylenediamine and oxalic acid as starting materials,DCQX was synthesized by two steps of cyclization and chlorination;methoxy ATIQ was cyclized with DCQX to obtain p-methoxy TNBG.2.UV spectrophotometry was used to detect the solubility of the derivative,and T-6 with good solubility was screened out.3.The anti-tumor activity of the target molecule was detected by CCK-8 method,and the corresponding IC₅₀ value was calculated.The inhibition rate of target molecules on tumor cells was determined at different doses,and T-6 with good pharmacological activity was screened out.In summary,four TNBG derivatives were synthesized from?4-methoxypHenyl?methanamine and benzene-1,2-diamine.The structure was confirmed by 1H-NMR,13C-NMR and MS.And the unexpected product has good drug-forming properties,laying a solid foundation for pre-clinical research of dextrozepam.