Synthesis And Antitumor Activity Of Fluoroquinolone Urea Compounds

Cancer is the disease that causes the highest mortality in humans.The most common methods currently used to treat cancer are surgery,chemotherapy and radiation therapy.However,chemotherapy has the defects of poor drug selectivity,serious side effects and poor tolerance,resulting in a significant decrease in the therapeutic index of chemotherapy drugs.Therefore,it is imperative to develop new anti-tumor drugs to overcome the defects of existing tumor therapeutic drugs.The development of new drugs is a high-risk,high-input complex intellectual creation process,in which the discovery and optimization of lead compounds is the key.The rational drug design strategy based on mechanism is the most economical and reliable means to modify the existing drug structure and discover the promising pioneers in the research and development of new drugs.As a widely used antibacterial drug in clinical practice,fluoroquinolone exerts an antibacterial action by inhibiting bacterial DNA gyrase and topoisomerase IV.Topoisomerases are also important targets for antitumor drugs.Therefore,the antibacterial activity of fluoroquinolone can be converted into antitumor activity by structural modification.Studies have shown that fluoroquinolone C-3 carboxyl?-COOH?is not a pharmacophore required for anti-tumor activity.It can be anti-tumor activity by replacing it with bioisosteric principle.It is an anti-tumor fluoroquinolone.The design of the molecule provides new ideas.Significant advances have been made based on targeted anti-tumor small molecule protein tyrosine kinase inhibitors?PTKIs?,and multiple compounds of different structural types have been successfully used in the clinical treatment of cancer with good targeted therapeutic effects.Therefore,this paper attempts to design the synthesis of 30 fluoroquinolone aryl ureas by using the important pharmacophore in the PTKIs,the urea-?-NH-CO-NH-?structure,for the isostere of the fluoroquinolone C-3 carboxyl group.Compounds,further developed a new way to modify the structure of anti-tumor fluoroquinolone,in order to achieve the superposition of active matrix by the migration and combination of the dominant backbone,to provide a basis for the renewal of the molecular structure of anti-tumor fluoroquinolone.In this paper,the clinical use of antibacterial fluoroquinolone drug?left?ofloxacin as a raw material,condensation with carbonyldiimidazole?CDI?to form?left?ofloxacin imidazole amide,following the aminolysis reaction with hydroxylamine hydrochloride to produce?left?ofloxacin hydroxamic acid,the key intermediate of fluoroquinolone-3-amine was formed by Lossen rearrangement reaction.The intermediate fluoroquinolone-3-amine is acylated with phenyl chloroformate to form N-phenoxyacyl quinolone-3-amine,and finally condensed with aromatic amine to obtain the desired fluoroquinolone aryl urea target compound.¹H NMR,LC-MS and IR confirmed.The in vitro anti-cell proliferation activities of the 30 target compounds synthesized against human pancreatic cancer cells Capan-1 and Mia-paca-2 and human gastric cancer cells BGC-823 and SGC-7901 were evaluated by MTT assay.The results showed that the anti-proliferative activity of the target compound against experimental cancer cells was significantly stronger than that of the parent ofloxacin and levofloxacin,containing 3-chloro?6g?,3,4-dichloro?8b?,2-methyl?8l?and 4-trifluoromethyl?8o?is stronger than other substituents.Among them,the compounds6g,6i,8b,8c,8j,8k,8l,8m,8o had an IC₅₀ of less than 10?g/mL for the four experimental cancer cell lines.In particular,6g,8b,8l,8o had IC₅₀ of less than 5?g/mL for the four experimental cancer cell lines,and the activity was comparable to the control antitumor drug doxorubicin,of which 8o was the best.At the same time,the results of hoechst 33342 staining showed that the compounds 6g and 8o dose-dependently inhibited the apoptosis of Capan-1 and Mia-paca-2,BGC-823 and SGC-7901,it was further confirmed that fluoroquinolones ureas could significantly inhibit the proliferation of human pancreatic cancer cells Capan-1,Mia-paca-2,human gastric cancer cells BGC-823 and SGC-7901,and promote the apoptosis of these four cells.The expression of caspase-3 protein in gastric cancer cell line BGC-823 was analyzed by immunoblotting.The results showed that up-regulation of caspase-3 protein expression might be one of the mechanisms of 6g and 8o inhibition of proliferation of gastric cancer cell line BGC-823..In summary,the fluoroquinolone aryl urea compound is used to enhance the anti-tumor of the fluoroquinolone C-3 carboxyl isostere using the dominant pharmacophore urea structure targeting the protein tyrosine kinase inhibitor.Activity,which provides a new structural modification idea and method for the antibacterial activity of fluoroquino to transform into anti-tumor activity.