Ester and hydroxamate analogues of methionyl and isoleucyl adenylates as inhibitors of methionyl-tRNA and isoleucyl-tRNA synthetases

Lee, Jeeyeon; Kang, Sang Uk; Kim, Su Yeon; Kim, Sung Eun; Kang, Mee Kyoung; Jo, Yeong Joon; Kim, Sung Hoon

doi:10.1016/s0960-894x(01)00095-6

Cited by 29 publications

(17 citation statements)

References 13 publications

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“…In general, mimicking the acyl-AMP intermediates by hydrolytically stable competitive inhibitors has proven a potent way of targeting the adenylate-forming enzymes from the different structural classes [12][13][14]. Focusing on aaRSs, enzymes which catalyse the activation and esterification of amino acids to their cognate tRNA, there have been many successful approaches to enhance the stability of the aminoacyl-adenylate intermediate by substitution of the mixed phosphoanhydride linker with a sulfur based isoster [15][16][17][18]. Amongst these the aminoacyl-sulfamate isosteres (Fig.…”

Section: Introductionmentioning

confidence: 99%

Acylated sulfonamide adenosines as potent inhibitors of the adenylate-forming enzyme superfamily

Ruysscher

Pang

Graef

et al. 2019

European Journal of Medicinal Chemistry

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The superfamily of adenylate-forming enzymes all share a common chemistry. They activate a carboxylate group, on a specific substrate, by catalyzing the formation of a high energy mixed phosphoanhydride-linked nucleoside intermediate. Members of this diverse enzymatic family play key roles in a variety of metabolic pathways and therefore many have been regarded as drug targets. A generic approach to inhibit such enzymes is the use of non-hydrolysable sulfur-based bioisosteres of the adenylate intermediate. Here we compare the activity of compounds containing a sulfamoyl and sulfonamide linker respectively. An improved synthetic strategy was developed to generate inhibitors containing the latter that target isoleucyl-(IleRS) and seryl-tRNA synthetase (SerRS), two structurally distinct representatives of class I and II aminoacyl-tRNA synthetases (aaRSs). These enzymes attach their respective amino acid to its cognate tRNA and are indispensable for protein translation. Evaluation of the ability of the two similar isosteres to inhibit serRS revealed a remarkable difference, with an almost complete loss of activity for seryl-sulfonamide 15 (SerSoHA) compared to its sulfamoyl analogue (SerSA), while inhibition of IleRS was unaffected. To explain these observations, we have determined a 2.1 Å crystal structure of Klebsiella pneumoniae SerRS in complex with SerSA. Using this structure as a template, modelling of 15 in the active site predicts an unfavorable eclipsed conformation. We extended the same modelling strategy to representative members of the whole adenylate-forming enzyme superfamily, and were able to disclose a new classification system for adenylating enzymes, based on their protein fold. The results suggest that, other than for the structural and functional orthologues of the class II aaRSs, the O to C substitution within the sulfur-sugar link should generally preserve the inhibitory potency.

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Section: Introductionmentioning

confidence: 99%

Acylated sulfonamide adenosines as potent inhibitors of the adenylate-forming enzyme superfamily

Ruysscher

Pang

Graef

et al. 2019

European Journal of Medicinal Chemistry

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“…Following the example of Cubist Pharmaceuticals ® the design of the starting materials 2 and 3 was kept identical. The synthetic procedure however was modified, and was largely based on the work by Lee et al, 13 Mandal et al 14 and most importantly Ohrui et al 15 (Scheme 3). Starting from ribose (10), the 2'-and 3'-hydroxyl groups were protected with an isopropylidene moiety and the 5'-hydroxyl with a p-anisyl-diphenylmethyl (MMTr) protecting group to afford 12.…”

Section: Design and Synthesis Of MCC And Albomycin Analogues Carrying A 2-carbon Linked Aryl-tetrazole As Adenine Substitutionmentioning

confidence: 99%

Microcin C and Albomycin Analogues with Aryl‐tetrazole Substituents as Nucleobase Isosters Are Selective Inhibitors of Bacterial Aminoacyl tRNA Synthetases but Lack Efficient Uptake

Vondenhoff¹,

Gadakh²,

Severinov³

2012

ChemBioChem

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In 1998, Cubist Pharmaceuticals patented a series of aminoacyl tRNA synthetase (aaRS) inhibitors based on aminoacyl sulfamoyladenosines (aaSAs), in which the adenine was substituted by aryl-tetrazole moieties linked to the ribose fragment by a two-carbon spacer. Although potent and specific inhibitors of bacterial IleRS, these compounds did not prove successful in vivo due to low cell permeability and strong binding to serum albumin. In this work, we attempted to improve these compounds by combining them with microcin C (McC) or albomycin (i.e., siderophore-drug conjugate (SDC)) transport modules. We found that aryl-tetrazole variants of McC and albomycin still lacked antibacterial activity. However, these compounds were readily processed by E. coli aminopeptidases with the release of toxic aaRS inhibitors. Hence, the lack of activity in whole-cell assays was due to an inability of the new compounds to be taken up by the cells, thus indicating that the nucleotide moieties of McC and albomycin strongly contribute to facilitated transport of these compounds inside the cell.

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“…In several instances, N-alkylation of hydroxamic acids 68, either by reactions with electrophiles [46,47] or using Mitsunobu alkylation of alcohols [48][49][50][51][52] [51,52]. O-Acylhydroxamates gave a mixture of N-and O-alkylkated products [51].…”

Section: Route Dmentioning

confidence: 99%

Solid-Phase Synthesis of Biologically Interesting Compounds Containing Hydroxamic Acid Moiety

Krchňák¹

2006

MRMC

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Chemical strategies developed for the solid-phase synthesis of hydroxamates are divided into four groups: (i) the traditional synthesis of hydroxamates via cleavage of resin-bound esters by hydroxylamine and its derivatives, (ii) introduction of hydroxamic acid moiety on the resin-bound precursor, (iii) transformation of polymer-supported hydroxylamine, attached to a solid supported linker either by oxygen (O-linking strategy) or by nitrogen (N-linking strategy), and (iv) synthesis of N-alkyl hydroxamates. The scope and limitation of individual approaches are discussed.

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Ester and hydroxamate analogues of methionyl and isoleucyl adenylates as inhibitors of methionyl-tRNA and isoleucyl-tRNA synthetases

Cited by 29 publications

References 13 publications

Acylated sulfonamide adenosines as potent inhibitors of the adenylate-forming enzyme superfamily

Acylated sulfonamide adenosines as potent inhibitors of the adenylate-forming enzyme superfamily

Microcin C and Albomycin Analogues with Aryl‐tetrazole Substituents as Nucleobase Isosters Are Selective Inhibitors of Bacterial Aminoacyl tRNA Synthetases but Lack Efficient Uptake

Solid-Phase Synthesis of Biologically Interesting Compounds Containing Hydroxamic Acid Moiety

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