P-57 PI 3-kinase阻害剤Wortmannin及びPI 3-kinaseのBiological toolの合成研究(ポスター発表の部)

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Wortmannin (1), isolated from Penicillium wortmannii Klocker, is an antifungal antibiotic and an antiinflammatry agent. These activities were partially explained through inhibition of myosin light chain kinase (IC_<50>=1.9μM). But recently, 1 was shown to inhibit phosphatidylinositol 3-kinase (PI 3-kinase) in lower IC_<50> (IC_<50>=5nM). PI 3-kinase is now very interesting for studies on signal transduction pathways of cell growth. Because of these interesting biological activities, especially its potent and specific inhibition of PI 3-kinase, we started synthetic studies on 1 and its derivatives for biological tools for PI 3-kinase. Our presentation is briefly summarized as below: 1) Toward our synthesis of 1, diol 5 should serve as a key intermediate which would provide 1 by the construction of the furan ring moiety. 5 was synthesized by the following procedure. Hydrocortisone (6) was converted into ene-ester 12 by the oxidative cleavages of 17-side chain and A ring. Iodolactonization of 12 gave iodide 13 as a sole product, however, which possessed the undesired configuration at C-1 position. The wrong configuration was clearly determined by NOE experiments. Accordingly, iodide 13 was transformed to 23 via 15, which was converted into lactone 24 with correct C-1 configuration under acidic condition. At this point, it was necessary to cleave the newly formed pyran ring in 24. 24 was epoxidized using MCPBA, followed by HCl aq. treatment leading to hemiacetal 21. After several efforts, cleavage of the pyran ring was achieved using Evans' reduction condition to give triol 25. Triol 25 was converted into key intermediate 5 in 6 steps. 2-1) 17-Acylated derivatives of 1 were prepared for the affinity column chromatography, and PI 3-kinase inhibitory activity of these derivatives was assayed. 2-2) Iodinated derivatives of 1 were designed and prepared for the radiolabelled compound, which would be used to detect PI 3-kinase sensitively. Now we are examining the introduction of the radioactive iodine atom in the compound 34.
天然有機化合物討論会の論文
1995-09-01

P-57 PI 3-kinase阻害剤Wortmannin及びPI 3-kinaseのBiological toolの合成研究(ポスター発表の部)

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