Synthesis And Photocontrol Activity Of Diazo Derivatives Of Anticancer Drug Axitinib

The most common toxic side effects of anticancer drugs are nausea,vomiting,consitipation,diarrhea,stomatitis,loss of appetite and hair loss.At present,the main methods for reducing the toxic side effects of drugs are the applications of targeted drugs,immunotherapeutics,prodrugs,sustained release,controlled-release drug delivery systerms and targeting drug delivery systerms.However,targeted drugs are difficult to design,and drug modifications may result in the decrease in activity.Feringa BL,a winner of the 2016 Nobel Prize in chemistry,first put forword the concept of photopharmacology in 2014.Photopharmacology refers to the use of light to remotely and reversibly control the structure of drug molecules to control drug activity,so that drugs could change between active and inactive states.Photopharmacology can be used to selectively activate or inactivate the drug activity in specific parts of the body,providing a new idea for reducing the toxic side effects.Axitinib is a small-molecule tyrosine kinase inhibitor marketed by Pfizer in 2012.Its main target is the vascular endothelial growth factor receptor VEGFR1-3,which is used in advanced renal cancer.Axitinib contains a stilbene-like structure and has trans and cis configurations.The trans configuration is a stable and active configuration in clinical applications.Stilbene tends to undergo structural cyclization by light irradiation,hence it is not suitable to be used to light-control activity or used as an optical switch for tyrosine kinase.Compared with the stilbene optical switch,the azobenzene optical switch has a lot of advantages,such as a large difference in the dipole moment of the cis-trans configuration,relatively high light steady state and quantum yield,fast photoisomerization and less photobleaching phenomenon.In order to obtain the compounds that have long-wavelength controlled and long-relaxation time and reversible light-controlling activity,the optical properties of axitinib and the differences in cis-trans configuration activity were studied first in this paper.Futhermore,ten axitinib derivatives were designed and synthesized,in which nitrogen-nitrogen double bonds were used to replace the carbon-carbon double bonds of axitinib,and substituted phenyl ring or five-membered pyrrole rings were used to replace pyridine rings.The main results are as follows:(1)Ten novel diazo dervatives of axitinib were synthesized and characterized by the high resolution mass spectrometry(HRMS),1H NMR and 13C NMR.(2)The optical properties of axitinib and its diazo dervatives were tested using an ultraviolet spectrophotometer.Compared to axitinib,the absorption wavelength of all dervatives was red-shifted,the half-life of all dervatives was shorter than that of axitinib.The half-life of the dervatives,in which the methoxy group is at the ?-position of the substituent benzene ring or have the N-methyl 5-membered pyrrole ring,are relatively long.(3)The experments of VEGFR-2 enzyme inhibitory activity showed that the most of compounds with five-membered pyrrole ring exhibited good enzyme inhibitory activity(IC50 is 100?300 nM)in the dark environment(the compounds mostly possess the trans configuration).The cis-trans isomers of axitinib displayed significant differences in activity after light-irradiation,the IC50 values was increased by 48-fold,but axitinib diazo derivatives showed no difference in activity because the half-life is too short.(4)In the HUVEC cell experiment,the dervatives that diazonium salt molecule linked to the alpha position of the 5-membered pyrrole ring were more active than axitinib in the dark environment.After light irradiation,one compound of the above devatives showed a significant difference in activity,but axitinib,5-membered pyrrole ring derivative TM2 and TM8 had slightly changes in activity.