Study On The Synthesis Of Brazilin’s Analogues And Their Inhibitory Activity On Bladder Cancer T24 Cell

Brazilin is a natural product isolated from Caesalpinia sappan,which has anti-inflammatory,anti-platelet,hypoglycemic,antibacterial,hepatoprotective,anti-tumor and other biological activities.For anti-tumor activity,studies have found that Brazilin has a novel effect on inhibiting bladder cancer cells,making it become a potential reagent for bladder cancer chemoprevention and treatment.The chemical characteristic of Brazilin is possessing a chroman skeleton cis-fused with a 2,3-dihydro-1H-indene moiety,including a hydroxyl group at the C-3 position,and three phenolic hydroxyl groups at C-7,C-12 and C-13 respectively.Because of its outstanding biological activity,Brazilin has attracted the interest of many scientific groups,and a lot of research has been done on its total synthesis and activity mechanism.However,the possible pharmacophore in the structure of Brazilin and the effect of structure on activity are hardly reported,and the lack of structure-activity relationship greatly limits the medicinal development of Brazilin.In this thesis,the analogs based on the core of brazilin were synthesized.On this basis,the inhibition experiment of bladder cancer T24 cells was carried out,and the structure-activity relationship of brazilin was initially explored.On the basis of not changing the ABCD core structure of Brazilin,three analogs of Brazilin are designed,namely Brazilin analog I with a-CH2OH chain structure at C-3position,Brazilin analog II with two phenolic hydroxyl groups at C-7 and C-8 position of D ring and Brazilin analog III with three phenolic hydroxyl groups at the C-5,C-6 and C-7positions on the D ring respectively.Using 3,4-dimethoxybenzyl alcohol as the starting material,through a series of chemical conversions,including S_N2 reaction,Mitsunobu reaction,Dess-Martin oxidation,Prins/Friedel-Crafts tandem reaction and demethylation reaction etc.,Brazilin analogs I(11 steps,total yield of 5%),II(10 steps,total yield of 10%),III(10 steps,total yield of 9%),were synthesized with obtaining the trifluoroacetate of the Brazilian I(11 steps,total yield of 4%)at the same time.With these analogs of Brazilin in hand,the thesis conducted an in vitro activity study on them in bladder cancer T24 cells,and found that Brazilin analog I and its trifluoroacetate had weak inhibitory effect on T24 cells,and Brazilin analogs II and III had stronger inhibitory effects on T24 cells.The experimental results preliminarily show that the substitution group at C-3 has a significant effect on the activity,and the addition of hydroxyl groups on the D ring did not help to improve the activity of brazilin in inhibiting T24 cells.