The Synthesis, Derivatization And Biological Activity Of An Active Marine Natural Product

Natural products with rich structure diversity and novelty provide an importanttemplate structure for drug research. However, limited resources of natural productimpact the follow-up research work of the template molecules. Semi-syntheticchemistry is one important way for solving the quantifing of natural product toexplore in depth the biological activity of the template molecules; Secondly, based onthe reactivity of the template molecules using diversity-oriented synthesis strategy tosynthesize “Natural product-like” compounds with structure diversity and noveltyaiming to discover new active molecules, is an important exploring field for thesynthesis of natural product.In the previous study, our research group obtained a new natural product7-isopropyl-1,4-dimethylazulene-3,5-dione from a gorgonian Muriceides collariscollected in South China Sea. This compound showed very strong antibacterialactivity against Vibrio anguillarum by the preliminary bioassay. Subsequently, thefurther studies on broad spectrum antibacterial tests for the compound encountered aserious difficulty due to the insufficient amount obtained from the marine organism.Meanwhile, azulene derivatives show good biological activities. So, the followingwork were carried out based on the guidance of the target-and diversity-orientedsynthesis strategy:1) cheap and easily obtained guaiazulene was used as the rawmaterial in a concise and efficient, environment friendly one-step reaction to firstlycomplete the optimization process of the target compound7-isopropyl-1,4-dimethylazulene-3,5-dione, through the seriatim-factorial experiments;2) reactionsof guaiazulene with bromine under three different conditions were designed tosynthesis a series of guaiazulene derivatives, and their biological activities, such asantitumor, anti-inflammation, antivirus, antibacterial, inhibition of quorum-sensingwere evaluated in vitro.The dissertation is composed of four chapters. In Chapter one, an overview of the development of drug research methods waspresented, the development of the target-and diversity-oriented synthesis and theirapplications in the synthesis of pharmaceuticals were described.In Chapter two, the research progress of azulene chemistry was brieflyintroduced, and overview of the chemical reaction and biological activity ofguaiazulene were presented.In Chapter three, the optimization process of the target compound7-isopropyl-1,4-dimethylazulene-3,5-dione was completed through the seriatim-factorialexperiments, and the the final reaction conditions were determined: when a solution of0.025mmol/ml guaiazulene in80%aqueous THF was treated with4equiv. ofbromide (with drop rate of0.1ml/min) and4equiv. of acetic acid at-5oC for3hours,the yield of7-isopropyl-1,4-dimethylazulene-3,5-dione was23.72%, almost2timesmore than the literature reported (8%).In Chapter four, twelve guaiazulene derivatives with varying skeleton weresynthesized using the diversity-oriented synthesis strategy, including monomers,dimmers and trimers. Their chemical structures were identified by using separationmeans such as TLC and HPLC, combined with a variety of spectroscopic techniques(NMR, MS, IR, UV), among which seven were new compounds and four were withnew azulene skeletons. Biological activities such as antitumor, anti-inflammation,antivirus, antibacterial, inhibition of quorum-sensing system were evaluated in vitroby selecting a variety of biological models. In the preliminary evaluation, compoundsGA,2b,2d,2e,3a,3b showed strong inhibitory activity against influenza virus H1N1;Monomer compounds1a-c and dimmer compounds2d,2e showed moderate activityagainst HeLa (human cervical carcinoma cell lines), HL-60(human promyelocyticleukemia cell lines) and K562(human chronic myeloid original leukemia cell lines);Compounds1a,1c,2d showed a certain activity against the quorum sensing system ofP. aeruginosa with the level of50μg/ml.In summary, this is the first report concerning targeted synthesis of7-isopropyl-1,4-dimethylazulene-3,5-dione, which could supply a convenient method for largepreparation of potent7-isopropyl-1,4-dimethylazulene-3,5-dione to further investigate the drug development possibility, and also provides a theoretical basis forthe futuremore comprehensive optimization process; A series of guaiazulenederivatives were synthesized by the use of the diversity-oriented synthesis strategy.Their biological activities were evaluated in vitro. New guaiazulene derivatives withanti-influenza virus H1N1activity were discovered and this research provides newactive structures for the study of antiviral drugs. This paper applied thediversity-oriented synthesis strategy to azulene chemical research, demonstrating thesignificance of the diversity-oriented synthesis method in the search for new highlyactive azulene derivatives.