Design, Synthesis And Activity Screening Of Aurora-A/PLK1 Dual-Targeting Inhibitors

The development of targeted anti-tumor drugs has gradually become the main force in the field of anti-tumor drug research,but there are complex network systems in the intracellular signal transduction pathways,only one cell signaling molecule is inhibited,the intracellular signals can often pass through other routes The conduction pathway ultimately has little effect on the function and state of the cells,resulting in poor therapeutic effects.Multi-targeted drugs can effectively regulate multiple complex conduction systems within cells,and do not completely eliminate the relationship between members of the signaling system.The resulting multi-targeted drug therapy can simultaneously regulate multiple aspects of the disease network system.It is not easy to produce drug resistance,and it has already begun to be applied in the treatment of many major diseases.A number of studies have confirmed that designing ligands that act on specific multi-targets has gradually become a hot topic for anti-tumor drug research in recent years.This study was based on the ability of both Aurora-A and PLK1 inhibitors to prevent similar and synergistic effects of centrosome maturation and the formation of double-spindle mitosis,and the inhibition of both alone can block mitosis in tumor cells.Blocking the features of cancer cell replication,combined with the key nucleus interaction modes of the existing pyrazole [3,4-b]pyridine Aurora-A inhibitors in the research group,and using the molecular fragments based mother-nuclear virtual screening and A novel Aurora-A/PLK1 dual-target inhibitor backbone structure with 6-amino-2-naphthoic acid as the parent core was found using a combination of computer-assisted drug design methods for the branched-chain design of receptor structures.Then,the simplest synthetic route for 6-amino-2-naphthoic acid compounds was designed and 35 compounds of this series were obtained through chemical synthesis and nuclear magnetic resonance mass spectrometry.The 35 compounds were preliminary ex vivo in human lung cancer cells(Calu-6),human colon cancer cells(HCT116),human breast cancer cells(MCF-7),and human non-small cell lung cancer cells(A549).Anti-tumor activity screening,finally found in these compounds have some good anti-tumor effect inhibitors,of which the best anti-tumor activity of compound C5 on cancer cells HCT116,Calu-6,A549,MCF-7 half of the inhibitory concentration reached 2.0 ?M,5.5 ?M,1.6 ?M,and 6.2 ?M,which are expected to become candidates for anti-tumor drugs with independent intellectual property rights in China.