Synthesis And Biological Activity Research Of Macrocyclic Bisbibenzyl And Their Derivative

Bryophyta are a kind of embryophyte with simple stem and rhizoids.90%of the liverworts possess special cell structure-oil body, which can synthesize and store unique terpenoids and aromatic compounds. Bisbibenzyls are a series of structurally simple phenolic natural products, which exhibit a variety of remarkable biological activities, including antifungal, antimicrobial, antioxidative, cytotoxic, insect antifeedant and multidrug resistance (MDR) reversal activities.In this paper, we described the total synthesis of riccardin D, a bisbibenzyl with C-C attachment. The intermediates were found with structural diversity in the synthesis process, and these compounds were purified by HPLC and detected by LC-CD. In addition, three brominated and aminomethylated derivatives were prepared based on the total synthesized riccardin D. Their antifungal activities against candida albicans and cytotoxic activities against KB, MCF-7and PC3cell lines have been preliminary evaluated. The bio-test results revealed that the brominated derivatives RCD-2exhibited excellent antiproliferative activity, with IC50value ranging from5.0to6.0uM, lower than its parent compound. As the most potent microtubule depolymerization agent, RCD-2was found to arrest cells at the G2/M phase of the cell cycle as determined by the flow cytometry assay in PC3cell line. The molecular modeling study revealed the possible binding mode of tubulin with RCD-2, which was consistent with colchicine. The remarkable biological profile and novel structure of these bisbibenzyl’s derivatives made them possible to be promising candidates for clinical development as chemotherapeutic agents. The attractive biological results motivated us to total synthesize plagiochin E, the isomer of RCD. After same structural modification, we got two intermediates and three derivatives. Biological activity was evaluated, and the result revealed that the brominated derivatives PLE-1exhibited excellent anticancer activity, with IC50value ranging from6.3to9.3μM, much lower than plagiochin E. At the same time, PLE-1and PLE-2also exhibited amazing antifungal activity against candida albicans, and the IC80value of two compounds were all0.5μg/ml, which were also significantly improved comparing with the activity of plagiochin E (32μM). In addition, marchantin C, a reported bisbibenzyl with C-O-C attachment, also exhibited superordinary anticancer activity. After total synthesized, halogenation and aminomethylation were carried out to get brominated and aminomethylated derivatives. In the synthesis process, we obtained the dimer of marchantin C and four derivatives. The activities of all the compounds were evaluated, MC-2and MC-3also exhibited excellent antifungal activities against candida albicans. The IC80value of two compounds were all0.5μg/ml, and also significantly improved compared with the activity of marchantin C (>128μg/ml).The excellent biological activities of bisbibenzyls and their derivatives play an essential role for developing new antibiotics and anti-cancer drugs.