Design,Synthesis And In Vitro Anticancer Activity Of Hydroxyl Anthraquinone Derivatives

Anthraquinone compounds are widely used in many fields.Often used as organic dyes,they are subsequently used in antiviral,antibacterial,and antitumour applications.Since the 1850s,a series of representative anthracyclines such as doxorubicin,clarin,mitoxantrone and daunorubicin have been synthesized one after another.These anthraquinone derivatives all have phenolic hydroxyl structures.With the development of anthracycline anticancer drugs,we have learned more about the toxicities and adverse reactions of anthraquinone derivatives in drug application.Therefore,drug researchers and developers try to design reasonable structures to obtain anthraquinone derivatives with high activity and low toxicity.In this work,we selected topoisomerase II（TOPO II）as the target,collected and sorted the anthraquinone compounds with certain anti-tumor activity in the literature,and studied their quantitative structure-activity relationship（QSAR）between the structural characteristics and anti-tumor activities,using the latest deep learning algorithm as a modeling tool to achieve certain results.Then we used TOPO II as the drug receptor target（The PDB Code is 1ZXM）,1,4-dihydroxyanthraquinone as the core structure of the ligand,using the docking calculation method,combined with the basic ideas of drug design such as skeleton transition and splicing principles,synthesized a series of 1,4-dihydroxyanthraquinone derivatives to obtain more pharmacologically effective TOPO II inhibitors and improve their anti-tumor activity,drug resistance and other aspects.We used 1,4dihydroxyanthraquinone as the starting material,connected the sulfonyl group to the 1,4 position of quinizarin,and applied advantage of its easy-to-leave property to synthesize it at position 1 through electrophilic and nucleophilic substitution reaction to a series derivatives of phenyl,alkyl chain and nitrogen heterocycle.Then the B series derivatives with phenyl and naphthyl were synthesized by Mike reaction at position 2.In this paper,the purity and structure of 29 compounds were determined by proton nuclear magnetic resonance spectrum,¹³C nuclear magnetic resonance spectrum and mass spectrometry.In this paper,the MTS method is used to conduct in vitro anti-tumor activity experiments on the synthesized anthraquinone derivatives.The experimental results show that the activities of the anthraquinone derivatives are higher than those of the anthraquinone core,the compound A15 and A20 show superior anti-tumor activity.Its IC₅₀ for DU145 is 16.88μM and 5.48μM indicates that by introducing heteroatom alkyl chain as the main pharmacophore.It not only greatly improves the fat solubility of the compound,but also significantly improves its biological activity.It provides a direction for our follow-up transformation of anthraquinone.