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Design, synthesis, and biological evaluation of inhibitors for N⁸-acetyspermidine deacetglase and spermidine N⁸-acetytransferase

Author

Tien Liang Huang, University of the Pacific

Date of Award

1989

Document Type

Thesis - Pacific Access Restricted

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Graduate School

First Advisor

David S. Fries

First Committee Member

James W. Blankenship

Second Committee Member

Madhukar Chaubal

Third Committee Member

Alice Jean Matuszak

Fourth Committee Member

Charles A. Matuszak

Abstract

Previous studies active-site-directed metal coordinating reagents and substrate analogues of (N⁸-AcSpd) have indicated that the catalytic mechanism of N⁸-AcSpd deacetylase involved a transition state metal. Several ω-amino substituted carboxylic acids were tested and results confirmed the probability of the deacetylase having a mechanism similar to the metalloproteases. Based on these results, several analogues of spermidine containing metal coordinating ligands were designed and synthesized. In addition, a potential transition state analogue of the nuclear enzyme, spermidine N⁸-acetyltransferase (N⁸-SAT) was also synthesized. All compounds were assayed in a 100,000g cytosol fraction form rat liver for their ability to inhibit the acetylation of radiolabeled substrate, [acetyl-³H]-N⁸-AcSpd. The apparent K_i (app K_i) values were determined from Dixon plots. The apparent K_m of N⁸-AcSpd for the cytosolic deacetylase is 11.0 μM.

Based on the results of this investigation and results obtained earlier in this laboratory, hypothetical models for the binding interactions of substrates and inhibitors to the active sites of N⁸-AcSpd deacetylase and N⁸-SAT are drawn schematically. The mechanism of catalysis of N⁸-AcSpd deacetylase also is proposed.

Pages

170

Recommended Citation

Huang, Tien Liang. (1989). Design, synthesis, and biological evaluation of inhibitors for N⁸-acetyspermidine deacetglase and spermidine N⁸-acetytransferase. University of the Pacific, Thesis - Pacific Access Restricted. https://scholarlycommons.pacific.edu/uop_etds/2179