Design and synthesis of inhibitors of N8-acetylspermidine deacetylase
Abstract
Analogues of N8-acetylspermidine (1) were synthesized as potential inhibitors of the cytoplasmic enzyme N8-acetylspermidine deacetylase. The compounds were assayed for their ability to inhibit the deacetylation of 1 in a cytosolic fraction from rat liver. The apparent Ki values were determined by Dixon plots. The apparent Km of 1 for this enzyme is 11.0 microM. It was found that compounds which lacked the N1 or the N4 of spermidine were less effective at competing for the enzyme than the substrate. All compounds with acyl substituents larger than acetyl were less potent inhibitors than the corresponding acetylated derivatives. Thus, the enzyme's selectivity as a deacetylase seems to be attributable to steric hindrance which occurs with larger acyl groups. The N8 of the substrate is not essential for its binding to the enzyme. Replacement of N8 with a CH2 group gives the ketone 14, which has an apparent Ki of 0.18 microM, 60-fold lower than the apparent Km of 1. The inhibitory potency of 14 is retained in compounds substituted at the N1 position. The N1,N1-dimethyl and the N1,N1-diethyl analogues (15 and 16) of 14 have apparent Ki values of 0.096 and 0.10 microM, respectively. These agents are the most potent inhibitors of N8-acetylspermidine deacetylase reported, and they are promising tools for use in determining the physiological function of N8-acetylspermidine deacetylation.
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Selective inhibitors have been developed that block mammalian PDAC activity.
“However, selective inhibitors have been developed that block mammalian PDAC activity111213.”
From Histone deacetylase 10 structure and molecular function as a polyamine deacetylase (2017) · cites this paper as [12]
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Background
- Authors
- Dredar, S. A., Blankenship, J. W., Marchant, P. E., Manneh, V., & Fries, D. S.
- Affiliations
- University of the Pacific (US)
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 1989-05
- Volume
- 32
- Issue
- 5
- Pages
- 984-989
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2087552818
- Cited by
- 16
- References
- 0
- Citations by year
- 2022: 1 · 2021: 1 · 2017: 1 · 2013: 1
- FWCI
- 0.64
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Polyamine Metabolism and Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
- Keywords
- enzyme inhibitors, N8-acetylspermidine, steric hindrance, acyl substituent effects, enzyme selectivity, substrate binding, rat liver cytosol
- MeSH terms
- Amidohydrolases, Animals, Binding Sites, Male, Rats, Inbred Strains, Spermidine, Structure-Activity Relationship, Drug Design, Rats
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