Synthesis And Antitumor Activity Of 1,4-Naphthoquinone Derivatives

Cancer is a common disease that seriously threatens human health.Its distribution is all over China and the world,and it has become an important cause of human death around the world.Cancer rates are on the rise globally as environmental pollution,aging populations and increasing smoking worsen.The treatment of cancer mainly includes surgical resection of local tumor tissue,adjuvant radiotherapy to remove residual cancer cells,and systematic chemotherapy to remove cancer cells scattered in normal tissues and metastatic cancer cells.At present,targeted therapy with anti-tumor drugs has become the mainstay of conventional cancer treatment.These include kinase inhibitors,monoclonal antibodies that target receptors on the surface of cancer cells,and cytotoxic drugs.Among them,enzyme inhibitors,such as Topo IIαand Bcr-Abl kinase inhibitors,have been well studied.It is also important to explore the molecular mechanisms by which drugs act on cancer cells to better understand how to balance the efficacy and toxicity of chemotherapy drugs.1,4-naphthoquinone and benzoic acid are small molecule aromatic ring compounds with a variety of biological activities,which have been widely used in many fields,including anti-tumor,antibacterial,anti-inflammatory,antiviral and so on.Naphthoquinone rings contain dicarbonyl groups,which are easily bound to different targets in tissues and organs through various interactions and show a variety of biological activities.Benzoic acid compounds easily form amide bonds,which in turn form hydrogen bonds and other forces with the target.1,4-naphthoquinone and benzoic acid have a variety of properties and functions due to their unique structures,which make them an important part of drug design and synthesis.In this study,1,4-naphthoquinone was selected as the lead compound.Naphthoquinone ring,phenylenediamine and benzoic acid were combined to form a new skeleton.The synthetic route:With 1,4-naphthoquinone as starting raw material,adding p-phenylenediamine or m-phenylenediamine,ethanol as solvent,reflux stirring,reaction to produce intermediate 2-（（4-aminophenyl）amino）naphtho-1,4-dione or 2-（（3-aminophenyl）amino）naphtho-1,4-dione;Then benzoic acid with different functional groups was activated with HATU in ice bath and dichloromethane was used as solvent.Finally,the intermediates and activated benzoic acid were stirred at room temperature to obtain new 1,4-naphthoquinone derivatives.After experimental screening,some of the obtained compounds were cultured in different proportions of acetonitrile and DMSO mixed solvents.All the designed and synthesized products were characterized by ¹H-NMR,¹³C-NMR,IR and HRMS to determine their structures,and some compounds were confirmed by X-ray single crystal diffraction.In this study,the inhibitory activity and apoptosis of 1,4-naphthoquinone derivatives on hepatoma cell Bel-7402 were studied.The results showed that most of the compounds had a certain inhibitory effect on Bel-7402.Compound 3a showed the best inhibitory activity with IC₅₀ of 8.64±3.09μM and apoptosis induction.The molecular docking study of 3a was also carried out.The results showed that compound 3a interacted with six Topo IIαamino acid residues（ALA167,ASN91,ASN163,ARG162,LYS378,ASN120）through hydrogen bonds.The hydrogen bond interaction with the four Bcr-Abl kinase amino acid residues（ASN322,GLN252,ARG367,TYR253）indicated that compound 3a had good bonding with Topo IIαand Bcr-Abl kinase and could be a multi-target ligand for anti-tumor.This paper contains 39 pictures,9 tables and 92 references.