Synthesis And Evaluation Antitumor Activity Of Cholic Acid-?-hydroxyphosphonate And Cholic Acid-?-aminophosphonate

Nowadays, cancer is a major problem in human health, medication is the basic and common treatment to that. However, the biggest limitation in medication lies in that it is difficult of general drug to identify normal cell and tumor cell, leading big side-effect to human body. Therefore, the design and synthesis of new target antitumor drugs has attracted more and more attention.Cholic acid, a kind of steroid compound synthesized in animal's liver, is an essential substance of enterohepatic circulation. Because of its unique amphipathicity, cholic acid can decrease surface tension between the lipid and the water and promote lipid to form mixed micells. So cholic acid exhibits a series of fascinating properties, such as various bioactivity and biocompatibility. Usually, cholic acid is regarded as drug targeting carrier for the reason that it is absorbed by the liver specifically. As an important part of organic phosphorus chemistry, phosphate esters and their derivatives have been used as pharmaceutical intermediate in the synthesis of antibacterial agents, herbicides and antitumor drugs because of the advantages of structure diversity, easy modifiation, good biocompatibility. In recent years, phosphate esters have been applied to the design and synthesis of novel antitumor drugs by scientists, and achieving better therapeutic effect.Based on the studies on cholic acid and phosphate esters and inspired by drug's targeted delivery, various phosphate esters were connected to cholic acid on the basis of association principle. By means of cholic acid's specificity absorption in the liver, the new compounds made phosphate ester which has pharmacological activity deliver to tumor cells selectively, for the goal of killing cancer cells selectively.Firstly, a series of ?-hydroxyphosphonates were designed and synthesized in this paper and then were introduced into the cholic acid via the esterification reaction to get cholic acid-?-hydroxyphosphonates derivatives. Secondly, ?-aminophosphonates were synthesized via the substitution reaction and reduction reaction with starting materials ?-hydroxyphosphonate to compare the effect of the ester group and amide bond on the bioactivity. Then 12 cholic acid-?-aminophosphonate derivatives, which had not been reported, were designed and synthesized via the acylation reaction with N,N'-Carbonyldiimidazole as condensing agent. Their structures were confirmed by IR, ¹HNMR, ³¹PNMR and HRMS. Finally, the anti-tumor activity against HepG2 of the cholic acid-?-hydroxyphosphonate derivatives and cholic acid-?-aminophosphonate derivatives were measured by the MTT assay method. The result proved that the compounds 4H?4I?4J?5j?5k and 5l showed more potent activities than Amonafide against HepG2. Besides, the anti-tumor activity of the cholic acid-?-aminophosphonate derivatives are better than that of the cholic acid-?-hydroxyphosphonates'.The innovation of the paper:?1? Cholic acid, as endogenous natural compound, can be absorbed by the liver specifically, exhibits good amphiphilicity and be harmless to humans. Regarding cholic acid as drug targeting carrier can kill cancer cells selectively.?2? In the synthesis of cholic acid-?-hydroxyphosphonate derivatives, we discussed the influence of different catalyst and solvent on reaction. Ultimately, DCC/DMAP acted as catalyst and THF as solvent, which is an effective way with fewer steps and better yields. In the synthesis of cholic acid-?-aminophosphonate derivatives, we discussed the influence of different condensing agent on reaction. By contrast, when CDI is used to condensing agent, post-processing of reaction is simple and highest yields were gained.?3? The effect on the anti-tumor activity against HepG2 between ester group and amide bond was compared.?4? 22 target compounds synthesized have not been reported in literature.