86 本態性高血圧症に関連するNa^+,K^+-ATPase阻害物質の合成研究(口頭発表の部)
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In the pathogenesis of essential hypertension, a circulating natriuretic factor with Na^+, K^+- ATPase inhibitory activity has been assumed to be participated. As one of these factors, a digoxin-like immunoactive substance (DLIS-2) was isolated from human plasma of renal patients. Although the tentative structure of DLIS-2 was proposed by Kenny et al., the exact assignment of the whole structure particularly of double bonds in acyl moiety remained to be done because of a small amount available from human source. We synthesized lysophosphatidylserine 10 with 19:4 (Δ^<5,8,11,14>) fatty acid as the candidate compound of DLIS-2 according to the following synthetic strategy. The acyl group of this molecule was introduced in the final step of this synthesis in order to facilitate the substitution of various fatty acyl groups. The formation of the phosphodiester linkage with a glycerol derivative and a serine derivative was performed by the monochloromonoamidite method followed by oxidation. The methyl group at the phosphate and the isopropylidene group were removed in this order to avoid a formation of the cyclic phosphate. The monoacylation with 19:0, 19:4, 20:4 (arachidonic) acids and nonadecatetraynoic acid respectively to 1-position of the glycerol moiety was performed by mixed anhydride method, and then Fmoc and Fm groups were removed by treatment with diethylamine. The synthetic compound 10 with 19:4 acyl group showed the most potent inhibitory activity for Na^+, K^+-ATPase from dog kidney with IC_<50> of 10^<-5> M indicating a strong possibility of the synthetic compound to be the endogenous hypertensive factor. The structure-biological activity relationship is also discussed.
- 天然有機化合物討論会の論文
- 1990-09-25
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