Synthesis Of Acitretin Acid Amide Derivatives By Acyl Chloride Method And Pharmacodynamics Investigation Of The Effects Of Leukemia Cells Differentiation Induced By 4-amino-2-trifluoromethyl-phenyl Acitretinate

Objective: Herein,we designed and synthesized a novel series of acitretin acid amide derivatives,which structure were dentified by 1HNMR,13CNMR and HR-MS. To investigate the proliferation inhibition and differentiation induction activities in K562 and NB4 cells,we study on the pharmacodynamics of the effects of leukemia cells differentiation induced by 4-amino-2-trifluoromethyl-phenyl acitretinate.Methods:1,The target compounds acitretin acid amide derivatives were prepared using acitretin and trifluoromethylphenyl derivatives as the starting materials by acyl chloride method, conveniently.2.Cell proliferation was assessed by MTT assay before and after the treatment with 4-amino-2-trifluoromethyl-phenyl acitretinate(ATPA) in vitro. Morphologic changes were observed after Wright's staining using inverted phase contrast microscope. The changes of growth curve induced by different concentrations of derivatives were analysed by cell counting. Cell differentiation indexs were analyzed by NBT reduction test. Cell cycle,the expression of the maturation specific cell surface markers CD71 of K562 cells and CD11b,CD13 of NB4 cells were detected by FCM. Results:1. All of the 5 new compounds which have not been reported in the literature were identified by 1HNMR,13CNMR and HR-MS.2. 4-amino-2-trifluoromethyl-phenyl acitretinate(ATPA) has powerful activity in inbibiting proliferation and inducing differentiation. After the treatment with ATPA,the growth of leukemic cells was inhibited in a dose-dependent and time-dependent manner. The NBT positive cell ratio,the expression level of the maturation specific cell surface marker CD11b of NB4 cells were increased while the expression level of CD13 was decreased,which was similar to acitretin. The longer,the greater the change. The proportion of cells in G0/G1 phase increased while S phase cells decreased.Conclusion:All of the 5 new compounds which have not been reported in the literature were synthesized. 4-amino-2-trifluoromethyl-phenyl acitretinate(ATPA) has powerful activity in inbibiting proliferation and inducing differentiation,whose mechanism will be explored on future.