Study On The Design, Synthesis And Antitumor Activity Of 4 - Substituted All - Trans Retinoic Acid Compounds

All-trans retinoic acid(,ATRA)has been used in clinical treatment of acute promyelocytic leukemia(APL),which has obtained good effect.The rate of Complete Remission in the APL patients can approach to 90%.However,the most patients obtained complete remission increased ATRA metabolism,mainly because ATRA’s rapid in vivo metabolism bv cvtochrome P450 enzymes.ATRA was quickly metabolized to 4-hydroxy ATRA that was further transformed into more polar metabolites.So ATRA loses biological activity in the treatment of APL.Studies found that introducing some groups at C-4 of ATRA should yield specific and potent inhibition of ATRA metabolism,which can maintain the pharmacological concentration of ATRA in vivo to differentiate tumor cells.According to Computer-Aided Drug Design,RARαwas taken as template and Gold software was used as docking software,the new compounds were docked.4-aromatic substituted ATRA gets high scores through the analysis of the docking scores.The electricity and three-dimension of aromatic groups were changed to research the changes of biological activity of ATRA.Based on these design ideas,benzylamino,benzyloxy and substituted phenylamino were introduced at C-4 of ATRA.22 compounds(sfy-1-sfy-22)have been designed and synthesized. These compounds are new compounds.The structures of these compounds have been characterized by the application of ~1H-NMR and MS.Finally,the activities of parts of synthesized compounds have been tested by the Trypan blue staining method and nitroblue tetrazolium method in vitro against NB4 cells(Human APL cells).