Total Synthesis And Antitumor Activity Of Polyoxygenated Xanthones

Nowadays, cancer is a highly prevalent disease leading to death. The search forimproved anticancer agents continues to be an urgent task in the drug discovery. Naturalproducts have been the most productive source of anti-cancer agents. PolyoxygentedXanthone has a broad pharmacological activity, such as antihypertensive, antioxidative,antithrombotic, anticancer and antifungal activities.6-Deoxyisojacareubin, Isojacareubin and Jacarelhyperol A were isolated by ourresearch group and following by the preliminary screening, all these natural compoundspresented better antitumor activity. The subject’s task was to complete the total synthesis ofthese three natural products and structurally similar natural products Ananixanthone andthen optimized the synthesis routes, so as to provide foundation for further activityvalidation research.Upon completing the total synthesis of6-Deoxyisojacareubin with about20%yield,all synthesized intermediates including6-Deoxyisojacareubin were evaluated for theirinhibitory against QGY-7703cell line and protein kinase C. Of these, compound1and6-Deoxyisojacareubin not only showed a moderate activity with IC₅₀values of39.61and 9.65μM respectively, but also showed a strong inhibitory activity to PKC. So we canconclude that its anti-tumor activity was related to PKC access.During the process of completing the total synthesis of Isojacareubin andAnanixanthone, we found that the substituted group in1-OH has a great influence on theClaisen rearrangement-cyclization direction, so the excellent site-selectivity of this Claisenrearrangement-cyclization reaction cascade was achieved by inserting a bulky p-tosylgroup into the free1-OH. Due to the presence of double bonds, we also explored severalconditions of removing the double benzyl group selectively and accomplish the totalsynthesis of Isojacareubin with about19%yield. At the same time, we also atempted tointroduce terminal alkynes side chain in a high yield in the case of intramolecular hydrogenbond existed and complete the total synthesis of Ananixanthone with an overall yield ofabout7%.At last, we devoted to complete the asymmetric total synthesis of Jacarelhyperol A.Several classic asymmetric reactions were attempted by us, such as Sharpless asymmetricdihydroxylation and Sharpless asymmetric epoxidation. Our study indicated that differentsubstituents on the xanthones nucles had a great influence on Sharpless asymmetricdihydroxylation. We also explored several protection and deprotection conditions to theprotecitive groups. After attempted several synthesized routs, we completed theconstruction of the basic racemic skeleton of this compound. At the same time, toinvestigate the correlation between the structures o f1,3,5,6-tetramethoxyxanthonederivatives and cytotoxicity against human hepatocellular carcinoma （HCC）, a series ofphenyl substituted tetramethoxy xanthone derivatives had been synthesized and theirpotential cytotoxic activity against HCC cell lines were investigated. Among thesederivatives, compound1,3,5,6-tetramethoxy-4-phenylxanthone was more potent thanpositive control5-fluorouracil （5-Fu） on QGY-7703and SMMC-7721cells with IC₅₀values of6.27μM,7.50μM and15.56μM,14.55μM, respectively.The effects of thepotent compounds on HCC cell apoptosis were further evaluated. Herein, the totalsynthesis and biological evaluation of these natural compounds and derivatives were reported.