Design And Synthesis Of RSL-3 Analogues

This paper mainly introduced the design and synthesis of a novel ferroptosis inducer.In this paper,we summarized a large number of literatures on the discovery and the induction mechanism of ferroptosis,and reviewed the relationship between ferroptosis and tumor.Then through the analysis of the induction mechanism,it was found that Gpx4might be an effective target to ferroptosis.Subsequently,through the related computer-aided drug design experiment docking analysis,we obtained the model of（1S,3R）-RSL3 interacting with Gpx4.In subsequent studies,it was found that Gpx4 could be associated with another ferroptosis-related protein system Xc-through effective design to synergistically induce iron death.In the initial stage,we designated（1S,3R）-RSL3 as a lead compound,and obtained DY-1a,DY-1b,DY-1c by bioisosteric and skeleton transition design.It was desirable to furtherly modify it to obtain a series of compounds with the same target and similar mechanism as（1S,3R）-RSL3.The former was docked by computer-aided drug design and found to have a similar effect to Gpx4 as the lead compound.In the process of reviewing the literature,it was found that（1S,3R）-RSL3 was covalently bound to other cysteine residues in addition to covalent binding to the target.For safety reasons,a new compound DY-4 was obtained by combining the important structural fragments of the system Xc-inhibitor erastin.Its chemical name was methyl-4-{{2-{4-[2-（4-chlorophenoxy）acetyl]Pip-erazin-1-yl}-N-（1H-indazol-3-yl）acetamido}Methyl}bezoic acid.After getting the structure of DY-4,we used discovery studio 3.5 to perform related docking calculations with Gpx4 and system Xc-to determine whether the design was reasonable.When DY-4 was docked with Gpx4,we found that the tension between the molecules also increased significantly due to the increase in molecular volume,which made the bonding state less than ideal.But when using DY-4 to interface with system Xc-,we got the good results.Compared with erastin,DY-4 had stronger affinity with the target,more clear the force,and the energy of the combined system was lower.Therefore,the design of the compound had achieved the desired goal.Finally,through a variety of modifications,we had designed a total of 32 compounds.After getting the structure,we obtained a synthetic route for the compound using reverse synthesis analysis.3-Aminocarbazole was prepared from o-fluorobenzonitrile and hydrazine hydrate in the route,and then reductively aminated with various benzaldehydes to obtain intermediate M2（a-c）.DY-1a,DY-1b,DY-1c were prepared by reacting intermediate M2（a-c）with chloroacetyl chloride.DY-1a,DY-1b,DY-1c were reacted with BOC piperazine,respectively,and the BOC protecting group was removed by methanolic hydrochloric acid to obtain intermediate M4（a-c）.Phenol and chloroacetic acid were reacted under basic conditions to obtain phenoxyacetic acid,and then chloroacetyl chloride was used to obtain phenoxyacetyl chloride.32 new compounds having a novel structure were finally obtained by dropping each of the substituted acid chlorides into a solution of M4 in methylene chloride at a low temperature.The structures of the 32compounds synthesized were confirmed by ¹H-NMR,¹³C-NMR and mass spectrometry,and the melting point of the compound was measured.