2005 Fiscal Year Final Research Report Summary
Development of Systematic Synthesis of Antitumor Annonaceous Acetogenins and Evaluation of Biological Activity
| Project/Area Number |
16590006
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Chemical pharmacy
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| Research Institution | Osaka University |
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Principal Investigator |
MAEZAKI Naoyoshi Osaka University, Graduate School of Pharmaceutical Sciences, Associate Professor, 薬学研究科, 助教授 (00229296)
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| Co-Investigator(Kenkyū-buntansha) |
TANAKA Tetsuaki Osaka University, Graduate School of Pharmaceutical Sciences, Professor, 薬学研究科, 教授 (40116059)
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| Project Period (FY) |
2004 – 2005
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| Keywords | Annonaceous Acetogenin / asymmetric synthesis / antitumor natural product / asymmetric alkynylation / reiterative process / stereodivergent synthesis / systematic synthesis / Anonaceae plant |
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| Research Abstract |
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 activity
We 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
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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 D
We 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
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