Design, Synthesis And Bioactivity Study Of Carboline And Pyrrole Marine Alkaloids And Therir Analogues

Cancer has been one of the serious diseases threatening human health. Marine natural products are important sources for development of new anti-cancer drugs. Many novel marine alkaloids exhibit the widespread biological activities including anti-tumor activity. Total synthesis and modification of the natural marine alkaloids become the hot spot in the medicine research and development. Although some marine alkaloids have specific and complex structures, their biological activities are not good enough to be clinically used. Therefore, the design and synthesis of analogues of marine alkaloids is important in drug research and development.Chemotherapy is one of the most important treatment methods for cancers. Extensive multidrug resistance (MDR) in cancer cells has been a major obstacle to successful cancer chemotherapy. Design and synthesis of the new tumor multidrug resisitance reversal agents is one of the key subjects in anti-cancer drug research and development.Theβ-carboline alkaloids, containing planar tricyclic aromatic system, are a large family of natural-occuring and synthetic alkaloids. Recently, these compounds attract a considerable attention due to their biological and pharmaceutical properties. The presence of planar tricyclic aromatic skeleton in theβ-carboline molecules enables them to bind to DNA base pairs of the tumor cell by insertion, which indicates that P-carboline alkaloids are DNA targeted compounds.Their antitumor biological effects might be due to the intercalation with DNA base pairs.In this dissertation, three series ofβ-carboline marine alkaloids including Hyrtiosulawesine, Eudistalbin A, Eudistomins Y]-Y7 and their analogues were designed and synthesized,their anti-tumor activities were evaluated; novel analogues of marine alkaloid Ningalin B,which showed potent multidrug resistance (MDR) reversal activities, were designed and synthesized; marine alkaloid Neolamellarin A was firstly synthesized. The first total syntheses of the (3-carboline marine alkaloids Hyrtiosulawesine, Eudistalbin A and Eudistomins Y1-Y7 were described. Twenty analogues of Hyrtiosulawesine, six analogues of Eudistalbin A and seven analogues of Eudistomins Y1-Y7 were designed and synthesized. The synthetic methods and reaction mechanisms of theseβ-carboline compounds were discussed, and economically feasible synthetic ways were developed.All of the target compounds were confirmed by 1HNMR,13CNMR and HRMS. The in vitro inhibitory activity of the target compounds were evaluated against the breast carcinoma cell line MDA-231.All of the tested compounds showed growth inhibitory activity against selected human tumor cell lines.The values'of IC50 of the Hyrtiosulawesine analogues 22c,22d,23b,20b,21b,21c,23a and 22a against breast carcinoma cell line MDA-231 are 1.05μM,1.77μM,2.58μM,2.67μM,4.43μM,4.44μM,4.50μM and 4.53μM respectively. The preliminary structure-activity relationships of these three types of compounds have been investigated.Twenty Ningalin B analogues targeted to P-gp were designed and synthesized. All.target compounds are novel and their structures are confirmed by 1H NMR, 13C NMR and HRMS.All the synthesized target compounds have not been reported yet in literatures except for Eudistomins Y1-Y6.A concise synthetic route has been used.The in vitro bioactivity test of the synthetic compounds showed that compounds 54,55,56,59,66,67 and 69 displayed significant MDR reversal activity on reversing paclitaxel resistance of breast cancer cell lines(LCC6MDR).Compound 56 displays the strongest modulating activity and causes about 18.2-fold hyper-sensitization of LCC6MDR towards paclitaxel.A synergy on modulating P-gp is noted when compound 56 and compound 66 were used together. A combination of 0.5μM of compound 56 and 0.5μM of compound 66 results in a 66-fold re-sensitization of LCC6MDR-towards paclitaxel(IC50=2.8 nM).The above data suggest that a cocktail chemotherapy including two modulators acting synergistically and an anticancer drug could likely be a novel, safe and highly potent way to treat MDR-cancer when other traditional treatment methods fail.All new permethyl Ningalin B analogues did not show any cytotoxicity to breast cancer cell lines(LCC6 and LCC6MDR)and the normal mouse connective tissue fibroblast(L929) even at a very high concentration(100μM) except for compound 59.The first total synthesis of marine natural product Neolamellarin A with pyrrole as the core skeleton was accomplished. The synthetic methods and reaction mechanisms were discussed, and a concise synthetic route has been used. The screening of its bioactivities is in progress.