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

  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},
  volume={21 15},
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
10 Citations
Design, Synthesis, and Evaluation of Polyamine Deacetylase Inhibitors, and High-Resolution Crystal Structures of Their Complexes with Acetylpolyamine Amidohydrolase.
Crystal structures of APAH-inhibitor complexes are determined at the highest resolution of any currently existing zinc deacetylase structure and thus represent the most accurate reference points for understanding structure-mechanism and structure-inhibition relationships in this critically important enzyme family. Expand
Binding of N8-Acetylspermidine Analogues to Histone Deacetylase 10 Reveals Molecular Strategies for Blocking Polyamine Deacetylation.
X-ray crystal structures of zebrafish HDAC10 complexed with eight different analogues of N8-acetylspermidine reveal interesting geometric changes in the metal coordination polyhedron that accommodate inhibitor binding. Expand
Structure and Function of the Acetylpolyamine Amidohydrolase from the Deep Earth Halophile Marinobacter subterrani.
The X-ray crystal structure of msAPAH, determined in complexes with 7 different inhibitors as well as the acetate coproduct, shows how the chemical strategy of Zn2+-dependent amide hydrolysis and the catalytic specificity for cationic polyamine substrates is conserved in a subterranean halophile. Expand
Histone deacetylase 10 structure and molecular function as a polyamine deacetylase
This work sets a foundation for studying the chemical biology of autophagy through the structure-based design of inhibitors that may also serve as new leads for cancer chemotherapy. Expand
Histone deacetylase 6 structure and molecular basis of catalysis and inhibition
Crystal structures ofCD2 from Homo sapiens and CD1 and CD2 from Danio rerio HDAC6 are reported and surprising new insight is revealed regarding changes in Zn2+ coordination and isozyme-specific inhibition. Expand
Synthesis of Trifluoromethyl Ketone Containing Amino Acid Building Blocks for the Preparation of Peptide-Based Histone Deacetylase (HDAC) Inhibitors
Trifluoromethyl ketones (TFMKs) are electrophilic moieties which hydrate readily in aqueous media to give geminal diols. This ability has been exploited for the development of histone deacetylaseExpand
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This review has enumerated over one hundred of inhibitors targeting various metalloenzymes and identified over ten kinds of fragments with different binding patterns, which will provide deep insights for the rational design of novel inhibitors targeting the metal-containing binding sites of specific proteins. Expand
Preparation of (perfluoroalkyl)alkane thiols via Zemplén deacylation of fluorous (perfluoroalkyl)alkyl thioacetates
Abstract Convenient and robust synthesis of (perfluoroalkyl)alkane thiols [(CnF2n+1(CH2)mSH); m/n = 3/4,6,8,10, 4a-d; m/n = 2/6, 8; m/n = 1/1,2,3,7,8H, 12a-e] was developed starting from commerciallyExpand
Nucleophilic Additions of Perfluoroalkyl Groups
The trifluoromethyl and perfluoroalkyl functional groups possess significant thermal, chemical, and metabolic stability, as well as high lipophilicity and electronegativity. These physicochemicalExpand
On the correction of calculated vibrational frequencies for the effects of the counterions — α,ω-diamine dihydrochlorides
Correctness factors to adjust the vibrational frequencies of a series of α,ω-diamines hydrochloride salts to account for the intermolecular interactions with the counterion suggest that transferability of the correction factors is possible not only for different diamines but also between different levels of theory. Expand


Design and synthesis of inhibitors of N8-acetylspermidine deacetylase.
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.
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
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.
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
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.
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.
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.
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.
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.
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