Synthesis and structure activity relationships of novel non-peptidic metallo-aminopeptidase inhibitors

Albrecht, Sébastien; Defoin, Albert; Salomon, Emmanuel; Tarnus, Céline; Wetterholm, Anders; Haeggstrom, J.Z.

doi:10.1016/j.bmc.2006.06.050

Cited by 29 publications

(17 citation statements)

References 49 publications

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“…We also effected cyclization of 8 to 2 by selective reduction of the carboxylic acid group of 8 with BH 3 , followed by lactonization with p-TsOH. 18 However, despite the fact that this process was one step shorter, we found that the yield for the conversion was lower (65% for transformation of 8 to 2 ), than the previously described activated ester method.…”

contrasting

confidence: 64%

An alternative synthesis and X-ray crystallographic confirmation of (−)-stepholidine

Gadhiya

Harding

2016

Tetrahedron Letters

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contrasting

confidence: 64%

An alternative synthesis and X-ray crystallographic confirmation of (−)-stepholidine

Gadhiya

Harding

2016

Tetrahedron Letters

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“…Because the calculation with a mixed quantum mechanics/molecular mechanics method was not successful, the CDOCKER software program [44] was used as a convenient program to estimate the structure of the AAP-8-HQ inhibitors (9)(10)(11)(12)(13)(22)(23)(24)(25), starting from the structure of the inhibitor-free AAP (Protein Data Bank, PDB, code 1RTQ) [45]. As a result, two complexation modes were suggested, as shown in Fig.…”

Section: The Relationship Between the Pk A Values Of 8-hq Derivativesmentioning

confidence: 99%

“…enzymes, reports on selective inhibitors of dinuclear Zn 2? enzymes such as AAP, cytosolic LAP, matallo-b-lactamase (subclasses B1 and B3), and alkaline phosphatase (ALP) are limited [23,24]. It has been reported that cytosolic LAP is concerned with canceration and metallo b-lactamases are multi-drug-resistance-associated proteins.…”

Section: Introductionmentioning

confidence: 99%

Potent inhibition of dinuclear zinc(II) peptidase, an aminopeptidase from Aeromonas proteolytica, by 8-quinolinol derivatives: inhibitor design based on Zn2+ fluorophores, kinetic, and X-ray crystallographic study

et al. 2012

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The selective inhibition of an aminopeptidase from Aeromonas proteolytica (AAP), a dinuclear Zn(2+) hydrolase, by 8-quinolinol (8-hydroxyquinoline, 8-HQ) derivatives is reported. We previously reported on the preparation of 8-HQ-pendant cyclens as Zn(2+) fluorophores (cyclen is 1,4,7,10-tetraazacyclododecane), in which the nitrogen and phenolate of the 8-HQ units (as well as the four nitrogens of cyclen) bind to Zn(2+) in a bidentate manner to form very stable Zn(2+) complexes at neutral pH (K (d) = 8-50 fM at pH 7.4). On the basis of this finding, it was hypothesized that 8-HQ derivatives have the potential to function as specific inhibitors of Zn(2+) enzymes, especially dinuclear Zn(2+) hydrolases. Assays of 8-HQ derivatives as inhibitors were performed against commercially available dinuclear Zn(2+) enzymes such as AAP and alkaline phosphatase. 8-HQ and the 5-substituted 8-HQ derivatives were found to be competitive inhibitors of AAP with inhibition constants of 0.16-29 μM at pH 8.0. The nitrogen at the 1-position and the hydroxide at the 8-position of 8-HQ were found to be essential for the inhibition of AAP. Fluorescence titrations of these drugs with AAP and an X-ray crystal structure analysis of an AAP-8-HQ complex (1.3-Å resolution) confirmed that 8-HQ binds to AAP in the "Pyr-out" mode, in which the hydroxide anion of 8-HQ bridges two Zn(2+) ions (Zn1 and Zn2) in the active site of AAP and the nitrogen atom of 8-HQ coordinates to Zn1 (Protein Data Bank code 3VH9).

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“…In another approach Albrecht et al synthesized various new derivatives of 3-amino-2-tetralone [192]. Several methyl ketone, substituted oximes or hydroxamic acids, phosphinic acids and hydrazides derivatives (exemplified by compounds 79e81, Fig.…”

Section: Tetralone Derivativesmentioning

confidence: 99%

Metallo-aminopeptidase inhibitors

et al. 2010

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Aminopeptidases are enzymes that selectively hydrolyze an amino acid residue from the N-terminus of proteins and peptides. They are important for the proper functioning of prokaryotic and eukaryotic cells, but very often are central players in the devastating human diseases like cancer, malaria and diabetes. The largest aminopeptidase group include enzymes containing metal ion(s) in their active centers, which often determines the type of inhibitors that are the most suitable for them. Effective ligands mostly bind in a non-covalent mode by forming complexes with the metal ion(s). Here, we present several approaches for the design of inhibitors for metallo-aminopeptidases. The optimized structures should be considered as potential leads in the drug discovery process against endogenous and infectious diseases.

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Synthesis and structure activity relationships of novel non-peptidic metallo-aminopeptidase inhibitors

Cited by 29 publications

References 49 publications

An alternative synthesis and X-ray crystallographic confirmation of (−)-stepholidine

An alternative synthesis and X-ray crystallographic confirmation of (−)-stepholidine

Potent inhibition of dinuclear zinc(II) peptidase, an aminopeptidase from Aeromonas proteolytica, by 8-quinolinol derivatives: inhibitor design based on Zn2+ fluorophores, kinetic, and X-ray crystallographic study

Metallo-aminopeptidase inhibitors

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