| Project/Area Number |
03453159
|
|---|
| Research Category |
Grant-in-Aid for General Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Research Field |
Chemical pharmacy
|
|---|
| Research Institution | RESEARCH FOUNDATION ITSUU LABORATORY |
|---|
Principal Investigator |
NATSUME Mitsutaka ITSUU LABORATORY DIRECTOR, 所長 (40087903)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
OKABE Kazuaki ITSUU LABORATORY RESEARCHER, 研究員 (80194380)
UTSUNOMIYA Iwao ITSUU LABORATORY RESEARCHER, 研究員 (60132784)
MURATAKE Hideaki ITSUU LABORATORY RESEARCHER, 研究員 (60142064)
|
|---|
| Project Period (FY) |
1991 – 1993
|
| Project Status |
Completed (Fiscal Year 1993)
|
| Budget Amount *help |
¥6,600,000 (Direct Cost: ¥6,600,000)
Fiscal Year 1993: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 1992: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 1991: ¥3,400,000 (Direct Cost: ¥3,400,000)
|
|---|
| Keywords | INDOLE SYNTHESIS / CHIRAL SYNTHESIS / INDOLE ALKALOID / CYTOTOXIC COMPOUND / MARINE SUBSTANCE / MITOSENE / PENDOLMYCIN / DUOCARMYCIN SA / DNAクロスリンク剤 / 藍藻含有インドール化合物 / 魚類食餌忌避剤 / 海綿アルカロイド / 新インド-ル合成法 / 阻害物質 / 麦角アルカロイド / 細胞毒性インド-ル化合物 / βーブロッカ-合成 |
|---|
| Research Abstract |
Previously we reported a new synthetic method for the preparation of indoles having various kinds of alkyl-and/or alkoxy-substituents at the benzene portion of the indole nucleus, starting from 2- or 3-substituted pyrroles. In the present research project, our new method was applied to an enantioselective synthesis of a variety of bio-active natural products of indole series, and the following successful results were obtained, culminating in a synthesis of an extremely potent anti-tumor antibiotic, duocarmycin SA.
1.Enantiomers of herbindoles A, B and C, cytotoxic constituents of an orange-colored sponge collected near Australia, were synthesized from a chirality-defined Diels-Alder adduct. This study established the absolute structures of the natural herbindoles, which had remained unknown.
2.Absolute structures of cis-, trans- and iso-trans-trikentrins B were also established by enantioselective syntheses of itself and enantiomers, starting from an intermedate of the above herbindole synthesis. These trikentrins are ingredients of another sponge in the ocean near Australia.
3.Antibacterial and antimycotic hapalindole O was synthesized from (R)-(-)-carvone.
4.Stereoselective synthesis of pendolmycin, an inhibitor of EGF-induced phosphatidylinositor turnover, was accomplished by incorporation of an optically active amino-alcohol into the position to be improved.
5.Mitosene derivatives related to mitomycins and FR 900482 were synthesized by condensation of a chiral aldehyde derived from an optically active amino acid and 4-alkoxyindoles obtainable using our indole synthesis.
6.A potent anti-tumor antibiotic, duocarmycin SA was synthesized by resolution of a racemic intermediate. It was shown that the non-natural enantiomer of duocarmycin SA exhibits also very strong anti-tumor activities.
|
