| Budget Amount *help |
¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1990: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 1989: ¥1,500,000 (Direct Cost: ¥1,500,000)
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| Research Abstract |
The labane diterpene forskolin, isolated from the roots of the Indian herb Coleus forskolii, has been shown to be hypotensive agent with spasmolytic, cardiotonic, and platelet aggregation inhibitory activity, and also demonstrated to be a unique and potent stimulator of the enzyme adenylate cyclase in various tissues. Owing to its therapeutic potential for glaucoma, congestive heart failure and bronchial asthma coupled with a substantial structural challenge, forskolin has elicited considerable synthetic attention. There have been synthesized more than 100 analogues from forskolin and its congeners, and through structure-activity relationships of them the region involving 1alpha-OH, 9alpha-OH, and 11-carbonyl has been suggested to be responsible for the above biological activities. We embarked upon an investigation directed towards the total synthesis of forskolin and its analogues otherwise difficult to prepare from natural forskolin with an aim to gain more information of structure-a
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citivity relationships and to differentiate a variety of activities forskolin exhibits. The activitiy of (<plus-minus>)-forskolin obtained by our total synthesis for adenylate cyclase in rat cerebral cortical membranes was half as potent as of natural forskolin, while (<plus-minus>)-1, 6, 7-trideoxyforskolin was totally inactive as we expected. Our attention was focused on the activity of (<plus-minus>)-6, 7-dideoxyforskolin, since it was not determined whether the presence of 6beta-OH and 7beta-OH is important or not for the activity. The result obtained with the synthesized molecule showed total inactivity, and so the presence of 6betaーOH and/or 7betaーOH was proposed to be crucial for the activity. With the above results in hand, we then directed our efforts to the total synthesis of (-)-forskol in natural form and the synthesis of its derivatives from the homochiral,versatile tricyclic lactone intermediate constructed by salient intramolecular DielsーAlder reaction of the butenolide. We have now found that the homochiral lactone with four asymmetric centers was efficiently constructe starting with the (S)-propargyl alcohol obtainable through (S)-BINAL-H reduction of the corresponding acetylenic ketone and successive recrystallization. The project on this line is goi Less
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