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Date of Award


Document Type


Degree Name

Doctor of Philosophy (Ph.D.)


Graduate School

First Advisor

David Fries

First Committee Member

Charles A. Matuszak

Second Committee Member

Fuad Nahhas

Third Committee Member

James W. Blankenship

Fourth Committee Member

John K. Brown


Ten N('8)-acetylspermidine analogues were synthesized. These compounds were used as active site directed agents to investigate the catalytic mechanism of N('8)-acetylspermidine deacetylase. This enzyme is present in the cytosolic fraction of rat liver homogenate. The Ki values for all the compounds were determined from Dixon plots. The results of this study show that these compounds act as competitive inhibitors of N('8)-acetylspermidine deacetylase. The Ki values of these compounds range from 29.2 to 0.00018 mM. The size of the active site was investigated by substitution of the acetyl group of N-acetyl-1,6-diaminohexane and N-acetyl-1,8-diaminooctane with larger groups. These modifications resulted in a decrease in the inhibitory activity. Compounds were made in which the length of the carbon chain between two terminal amino groups was varied. It was found that a six carbon separation is needed for optimal activity. Bioisosteric replacement of N('4) of N('8)-acetylspermidine with a -CH(,2)- group resulted in a decrease in the potency of the compound compared with N-acetyl-1,6-diaminohexane. On the other hand, bioisosteric replacement of the N('8) of N('8)-acetylspermidine with a -CH(,2)- group resulted in a large increase in the inhibitory activity. The Ki value for this compound (Ki = 0.00018 mM) is lower than the Km of the enzyme (Km = 0.01m mM). Results obtained from this project and other results obtained in our laboratory were used to draw a hypothetical model for the active site of N('8)-acetylspermidine deacetylase.





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