Synthesis And Anti-tumor Activity Of Retinoic Acid Derivatives

At present, retinoids have found clinical utility in the treatment of skin disease and cancer. But it has also been suffered from two main disadvantages: chemoresistance to the drugs can occur easily, and can lead severe toxic side effects. Therefore, it is necessary to develop other retinoids derivatives with better clinical efficacy.Objective: Herein, we designed and synthesized a novel series of retinoids derivatives with an electron withdrawing units– trifluoromethylphenyl. This research work dealed with the chemical modification of ATRA and acitretin, designed and synthesized 23 new chemical modified retinoids analogues. All of the above compounds were identified by 1HNMR, 13CNMR and HR-MS. Subsequently, the observation of a new type of synthetic derivatives of retinoic acid on leukemia cell line NB4 cells induced by inhibition proliferation and differentiation activity, selected retinoids derivatives with pharmacological activity.Methods: The target compounds retinoic ester derivatives were prepared using ATAR or acitretin and trifluoromethylphenyl derivatives as the starting materials by condensation with DCC and DMAP, conveniently. By the synthetic procedure of retinoic amide derivatives, we have improved the operation method in the reference, and used DMAP?PTSA (para-toluenesulfonic acid, PTSA) as catalyst. An improved DCC condensation with DMAP p-toluenesulfonate substitute DMAP as the catalyst was described and applied to the synthesis of retinoic amide derivatives. The side reaction that converts RA to unreactive N-retinoylurea was completely suppressed. The reaction proceeds under mild conditions and is favored in the acidylation of alcohol. All of the above compounds were identified by 1HNMR, 13CNMR and HR-MS. Subsequently, the anti-tumor activity of these RA derivatives against leukemia cell lines--NB4 was evaluated and the inducing differentiation activity was explored. The new role of retinoic acid derivatives on NB4 cells by MTT cell proliferation assay. NBT reduction analysis of the experimental cell differentiation indicators. FCM analysis of cell cycle changes.Results:1. All of the 23 new compounds which have not been reported in the literature were identified by 1HNMR, 13CNMR and HR-MS.2. After treatment with some of ATRA derivatives for 72h, the inhibited proliferation of NB4 cells in a dose-dependent increase in the role of 10-5 mol/L the strongest inhibitory effect. Derivatives of retinoic acid (10-5 mol/L) induced differentiation of activity were observed in the oil to the granulocyte NB4 cell differentiation and maturation changes, NBT-positive cells increased. Flow cytometric analysis showed that some of the compounds allowed the expression of G0/G1 phase cells increased, S phases cells reduced, showed G1 phase arrest.3. After treatment with some of acitretin derivatives for 72h, the MTT assay indicated that some of the new compounds can inhibit tumor cell growth significantly. Flow cytometric analysis showed that Some of the compounds allowed the expression of G0/G1 phase cells increased, showed G1 phase arrest. The results indicated that some of the new compounds exhibited inducing differentiation activity.Conclusion: All of the 23 new compounds which have not been reported in the literature were synthesized. The anti-tumor activity results show that some of the new synthetic compounds indicated significant role in tumor cell differentiation. The biological data indicated that the amino and hydroxy group of the phenyl might be essential groups to the anti-tumor activities of retinoids derivatives at the same time. And simply the end of retinoic acid in the esterification of carboxyl group to have been without the introduction of amino compounds, although it can enhance its inhibitory effect on tumor cells, but can not be effectively induced differentiation. 4-HPR hint to the starting point for the development of a better role in inducing tumor cell differentiation of retinoic acid-type drugs is of great significance.