Design,Synthesis And Biological Evaluation Of Hydroxyanthraquinone Derivatives As Potential Antitumor Agents In Vitro

Anthraquinone compounds are widely used.Anthraquinone are often used as natural dyes and are later valued for their wide medicinal value.For example,they have antibacterial,antiviral,antitumor,anti-aging,anti-ultraviolet effects.In addition,Anthraquinone compounds are the most widely used broad-spectrum antitumor drugs.Since the middle of the last century,the famous drugs such as doxorubicin,clarithromycin,daunorubicin,erythromycin and mitoxantrone have been developed.Common features of the above antitumor agents are both hydroxy substituted anthraquinone compound.However,with the popularity of anthracycline anticancer drugs,their toxicity in the kidney and heart has been paid more and more attention,which greatly limits the application of such drugs.Therefore,many scholars have been working to obtain derivatives with better activity and lower toxic side effects through rational structural modification.In the study of this paper,we successfully synthesized a series of A derivatives containing thienyl and substituted phenyl groups by using modified Marschalk reaction with 1,4-hydroxyanthraquinone(Quinizarin)as the starting material,and then using drug combination principle nitrogen mustard group with alkylation was introduced on the basis of some of the A series compounds.The hydroxyanthraquinone moiety provides a potential substrate for DNA insertion and bioreduction activation,and the nitrogen mustard alkylation group confers cytotoxicity.In order to comprehensively study the structure-activity relationship,we introduced a sulfonyl group at two hydroxyl positions of the quinizarin.The 37 target compounds of designed and synthesized in this paper were structurally confirmed.In vitro antitumor activity indicated that all derivatives showed stronger cytotoxicity than quinizarin,which is confirmed by the molecular docking scoring function.Compounds A1 and A4 exhibited broad-spectrum antitumor activity and were non-toxic to normal liver tissue cells L02 with certain selectivity.Further study of mechanism of action showed that compounds A1 and A4 could induce apoptosis to some extent.Confocal drug tracking showed that Al could enter the cytoplasm in large quantities and cause nuclear shrinkage and deformation.Due to the fluorescent effect compounds,further studies are continuing.