| Budget Amount *help |
¥4,200,000 (Direct Cost: ¥4,200,000)
Fiscal Year 1989: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 1988: ¥3,200,000 (Direct Cost: ¥3,200,000)
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| Research Abstract |
The cardiac glycoside, proscillaridin, has been widely used in the therapy of congestive heart failure. However, this drug shows very narrow concentration of PIE and sometimes causes arrhythmia. As an extension of our continuing programs directed towards the development of new proscillaridin analogs with a lower risk of toxicity, we carried out the chemical transformations of 6-deoxy-mannose and unsaturated lactone moieties of proscillaridin. The biological activities of the derivatives were studied by the use of a Na, K-ATPase preparation from dog kidney. In addition, monensin, which is a naturally occurring ionophore and has a potent Na ion permeability, was chemically modified by amino acids, because permeability of Na ion into the cell is supposed to be deeply concerned with a cardiac activity.
Nitration of proscillaridin with HNO_3-AcOH gave five O-mono or multisubstituted esters which were readily separated by silica column. 1,4-Cyclo-additions of proscillaridin with methyl vinyl ketone or methyl acrylate yielded two [4+2]cycloadducts, which were separated by HPLC and confirmed based on CD, ^1H-NMR and NOE. Isomeric cycloadducts aromatized at the high temperature to give acetophenone or methyl benzoate. Of these compounds, 2,4-0-dinitro ester and acetophenone showed a potent enzyme-inhibitory activity.
Na ion permeability of monensylamino acids measured by ^<23>Na-NMR, was found to be comparable to that of proscillaridin. However, none of monensylamino acids showed the biological activities. Therefore, these compounds were converted to more lipophilic macrocyclic lactohes, which were potent in Na ion transporting ability and consequently are now under advanced evaluation.
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