Synthesis, Inhibitory Activity Evaluation Of Purine Derivatives And Cyclic Phosphonate Prodrugs

Purine does not exist in nature, but its derivatives are widely distributed in nature. Purine are the part of DNA and RNA bounding with specific pyrimidine. They exert the important function in the biological processes. Purine and its derivatives are a class of important pharmaceutical compounds with their significant physiological and pharmacological properties. Many nucleoside analogues have been investigated for their antiviral(especially anti-Aids) and anticancer activities. There are three position can be substituted for purine, except nucleoside drugs with glycosylation at9-position. The2,6or8-position substituted purine derivatives have been shown to have biological activitys of antiviral, antitumor, anti-parasite, and so on. A series of2,6-substituted purine derivatives by R-NH, typically "Reversine", have been shown excellent biological activity.Therefore, the structure modification of purine ring and pharmaceutical activity evaluation has been the focus of the study of purine compounds.In this dissertation, twelve compounds of2-substituted anilino-6-cyclohexylamino purine (compounds33a～331), four compounds of2-substituted anilino-6-n-butylamino-purine (compounds34a-34d), and nine compounds of6-arylamino purine derivatives (compounds63a-63i) were designed and synthesized. The synthetic methods with a high yield, mild reaction conditions and the purified product of2,6-disubstituted purine derivatives were explored. The microwave radiation were used for the synthesis of purine derivatives. A practical synthesis of2-substituted derivative compounds32a,"Reversine"(32e) and6-substituted purine derivatives40～44,47by microwave radiation rapid were investigated. The synthesized compounds of purine derivatives bonding with different alkylamino-, substituted anilino-, morpholino anilino-were evaluated for their inhibitory activities against liver cancer cell lines of Bel-7402. Moderate antitumor activity were exhibited of2-(4-benzyl-O-phenylamino)-6-cyclohexylamino-purine (compound33g),2-(4- chloro-phenylamino)-6-n-butylamino-purine (compound34b) and2-(4-morpholinoamino)-6-(4-chloro-phenylamino)-purine(compound63i). Their IC50values against liver tumor cell line Bel-7402were13.0μM,40.8μM and27.7μM respectively.A group of novel modified purine derivatives containing phenoxy glycosides were designed and synthsized in this dissertation. Four kinds of glycosylation donor (glucose, galactose, lactose, xylose) were bonding with purine ring at2-position in available order of reaction. Four2-(4-O-glyco-phenylamino)-6-(cyclohexylamino) purine derivatives (compounds36～39) were synthesized successfully. Moderate antitumor activity were exhibited, based the sugar group of glucose group (compound36), and galactose (compound37), xylose (compound39). Their IC50values against liver tumor cell line Bel-7402were82.8μM,38.2μM and75.3μM respectively.Six purine derivatives containing a sulfur atom at6-position(compounds62b-62g) or9-position (compounds45) were designed and synthesized. Moderate antitumor activity were exhibited of compound62b and62c, with54.71%and66.86%inhibition rate respectively at1μM concentration against liver tumor cell line Bel-7402. The strategy of the synthesis were explored for the developing of purine derivatives.Prodrugs has been reported to increase the bioavailability, enhance targeting, reduce the toxicity and side effects of drugs. Typically the prodrug, HepDirect, a class of novel cyclic1-aryk-1,3-propanyl phosphonate prodrug dased nucleoside is attributed to the effective anti-HIV activity, and good chemical and enzyme stability, does not increase the cytotoxicity. The pharmacotherapy of cancer is progressing rapidly and new anti-cancer drugs is emerging prominently. The anti-cancer drugs of Camptothecin, Paclitaxel and Vitamin A have been believed to be the most important discovery in the90’s. Campothecin cannot be dissolved in water. The clinical therapeutic of the sodium salt of Campothecin indicated the high toxicity and side effects. So, the structural transformation of Camptothecin were investigate widely. The cyclic phosphate prodrugs of Camptothecin were prepared from10-hydroxycamptothecin by condensation of ketoester reduction, silicon etherified and chiral separation reaction in this dissertation. The chiral synthesis methods of the chiral intermediate1-aryl-1,3-propanediol were explored.1-Aryl-1,3-propanediol were prepared by chiral reduction reaction in chiral ionic liquid alkylimidazole-L-proline salts. The optical purity of the product was82%. Forty-two target compounds, including thirty-nine novel compounds, were synthesized. Their structures were determined by1H NMR,13C NMR and MS.