Synthesis and evaluation of N⁸-acetylspermidine analogues as inhibitors of bacterial acetylpolyamine amidohydrolase.

@article{Decroos2013SynthesisAE,
  title={Synthesis and evaluation of N⁸-acetylspermidine analogues as inhibitors of bacterial acetylpolyamine amidohydrolase.},
  author={C. Decroos and C. Bowman and D. Christianson},
  journal={Bioorganic \& medicinal chemistry},
  year={2013},
  volume={21 15},
  pages={
          4530-40
        }
}
Polyamines are small essential polycations involved in many biological processes. Enzymes of polyamine metabolism have been extensively studied and are attractive drug targets. Nevertheless, the reversible acetylation of polyamines remains poorly understood. Although eukaryotic N(8)-acetylspermidine deacetylase activity has already been detected and studied, the specific enzyme responsible for this activity has not yet been identified. However, a zinc deacetylase from Mycoplana ramosa… Expand
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References

SHOWING 1-10 OF 64 REFERENCES
Design and synthesis of inhibitors of N8-acetylspermidine deacetylase.
TLDR
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, and all compounds with acyl substituents larger than acetyl were less potent inhibitors than the corresponding acetylated derivatives. Expand
Inhibition of N8-acetylspermidine deacetylase by active-site-directed metal coordinating inhibitors.
TLDR
Results suggest that the catalytic mechanism of the enzyme requires a transition state metal and free sulfhydryl groups for activity, and that the enzyme is inhibited by metal chelators, several omega-amino-substituted carboxylic acids, and some thiol reagents. Expand
Inhibitors of polyamine metabolism: Review article
TLDR
Evidence of induction of both PAO and PAO-h1/SMO in response to polyamine analogue treatment, suggests the analogues may become an important part of future chemotherapeutic and/or chemopreventative regimens. Expand
Synthesis of a new trifluoromethylketone analogue of l-arginine and contrasting inhibitory activity against human arginase I and histone deacetylase 8.
TLDR
It is suggested that 10 represents a new lead in the design of an amino acid or peptide-based inhibitor of histone deacetylases with simpler structure than previously studied trifluoromethylketones. Expand
Evaluation of functional groups on amino acids in cyclic tetrapeptides in histone deacetylase inhibition
TLDR
Among the functional groups, methoxymethylketone moiety showed as potent inhibition as the hydroxamic acid, and it was confirmed that borate, trifruoromethylketone, and 2-aminoanilide are almost inactive in HDAC inhibition. Expand
A selective inhibitor of N8-acetylspermidine deacetylation in mice and HeLa cells without effects on histone deacetylation.
TLDR
It is suggested that APAH has a relatively selective inhibitory effect on N8-acetylspermidine but not histone deacetylation, as well as in vitro studies, which suggested this could be a potent, effective inhibitor in vivo. Expand
Structure of prokaryotic polyamine deacetylase reveals evolutionary functional relationships with eukaryotic histone deacetylases.
TLDR
The structure of APAH is the first of a histone deacetylase-like oligomer and reveals that an 18-residue insert in the L2 loop promotes dimerization and the formation of an 18 Å long "L"-shaped active site tunnel at the dimer interface, accessible only to narrow and flexible substrates. Expand
Differential inhibition of histone and polyamine acetylases by multisubstrate analogues.
TLDR
Rabbit antiserum to homogeneous rat liver spermidine/spermine N1-acetyltransferase had no effect on the activity of a crude nuclear extract from rat liver, indicating that its sperMidine acetylating capability is not related to the cytosolic sper midine/ spermine S1- acetyltransfer enzyme induced by hepatotoxins. Expand
Design, synthesis, and biological activity of boronic acid-based histone deacetylase inhibitors.
TLDR
The findings indicate that these boronic acid derivatives represent an entry into a new class of HDAC inhibitors, and the results of Western blot analysis indicated that the cancer cell growth-inhibitory activity of compounds (S)-18, 20, and 21 is the result ofHDAC inhibition. Expand
Structure, mechanism, and inhibition of histone deacetylases and related metalloenzymes.
TLDR
Structural comparisons among HDACs and HDAC-related deacetylases reveal a conserved constellation of active site residues, suggesting a common mechanism for the metal-dependent hydrolysis of acetylated substrates. Expand
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