2000 Fiscal Year Final Research Report Summary
Synthesis of viridiofungins and zaragozic acids, cholesterol synthesis inhibitors
| Project/Area Number |
09470487
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| Research Category |
Grant-in-Aid for Scientific Research (B).
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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 | Nagasaki University |
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Principal Investigator |
HATAKEYAMA Susumi Nagasaki University, Faculty of Pharmaceutical Sciences, Professor, 薬学部, 教授 (20143000)
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| Project Period (FY) |
1997 – 2000
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| Keywords | viridiofungin / zaragozic acid / sphingo lipid synthesis inhibition / antibacterial activity / squalene synthase inhibition / asymmetric synthesis / dialkenylcarbinol / dihydroxylation |
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| Research Abstract |
Both viridiofungins and zaragogic acids have attracted much attention as leading compounds for developing an effective cholesterol lowering drug because of their potent squalene synthase inhibitory activity. In this research, we aimed to develop efficient methods for the syntheses of these families of compounds.
Viridiofungin A was isolated from a strain of Trichoderma viride Pers.(Fungi, Hyphomycetes) together with viridiofundin B and C.These viridiofungins have unique structures consisting of a common citric acid moiety having C-16 long chain and an aromatic amino acid residue such as tyrosine, phenylalanine, and tryptophane. However, the absolute structures of these compounds were not determined. In this research, we achieved the first synthesis of viridiofungin A trimethyl ester which allowed us to determine its absolute configuration to be 3S, 4S, 2'S.
For zaragozic acids, we envisaged a new strategy which relies on unprecedented double dihydroxylation of dialkenylcarbinols. We first examined double hydroxylation of various dialkenylcarbinols to check the diastereoselectivity. As a result, we found that this reaction took place with moderate to excellent diastereoselectivity and the major diastereoisomer possessed desirable configuration for the synthesis of zaragozic acids. Now we are carrying out the synthesis of zaragozic acid A based on the above-mentioned strategy.
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