Development of Systematic Synthesis of Antitumor Annonaceous Acetogenins and Evaluation of Biological Activity

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We have investigated a synthesis of Annonaceous acetogenins possessing a potent cytotoxicity against various human cancer cell lines as well as a development of highly potent derivatives. As a result, a first total synthesis of representative mono- and bis-THF acetogenins, murisolin and longimicin D, respectively, was accomplished. Furthermore, by applying our systematic synthesis of the poly-THF cores, two diastereomeric murisolin congeners were synthesized and their biological activity was evaluated.1)Synthesis of Murisolin Derivatives and Evaluation of Biological activityWe have already developed systematic synthesis of the poly-THF cores. As an extension of the research, we applied the methodology to a first total synthesis of mono-THF acetogenin, murisolin. We established a method for a connection of the THF segment and the γ-lactone segment that is important process for a synthesis of Annaceous acetogenins. As a result, first total synthesis of murisolin was accomplished. In addi … More tion, two diastereomeric isomers of murisolin were synthesized in a similar manner. Three murisolins were evaluated by the cell-growth inhibition profile and COMPARE analysis. Their finger prints against 39 kinds of human cancer cell lines were collected. These finger prints were statistically compared with each other as well as with known anti-cancer drugs having different action mechanisms.2)First Total Synthesis of Longimicin DWe investigated a total synthesis of bis-THF Annonaceous acetogenins, longimicin D, which possesses a potent cytotoxicity against human pancreatic cancer call. The bis-THF ring cores having congested stereogenic centers were constructed with high diastereoselectivity by applying previously developed systematic synthesis of the poly-THF cores. Then, we examined appropriate linker segment to connect the bis-THF and γ-lactone segments. Consequently, (3R)-10-benzyloxy-3-(methoxymethoxy)dec-1-yne was found to be the most suitable linker segment. Finally, three segments were efficiently assembled and a first total synthesis of longimicin D was achieved. Less