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Facile Access to Fe(III)-Complexing Cyclic Hydroxamic Acids in a Three-Component Format.

ABSTRACT: Cyclic hydroxamic acids can be viewed as effective binders of soluble iron and can therefore be useful moieties for employing in compounds to treat iron overload disease. Alternatively, they are analogs of bacterial siderophores (iron-scavenging metabolites) and can find utility in designing antibiotic constructs for targeted delivery. An earlier described three-component variant of the Castagnoli-Cushman reaction of homophthalic acid (via in situ cyclodehydration to the respective anhydride) was extended to involve hydroxylamine in lieu of the amine component of the reaction. Using hydroxylamine acetate and O-benzylhydroxylamine was key to the success of this transformation due to greater solubility of the reagents in refluxing toluene (compared to hydrochloride salt). The developed protocol was found suitable for multigram-scale syntheses of N-hydroxy- and N-(benzyloxy)tetrahydroisoquinolonic acids. The cyclic hydroxamic acids synthesized in the newly developed format have been tested and shown to be efficient ligands for Fe3+, which makes them suitable candidates for the above-mentioned applications.

SUBMITTER: Chupakhin E

PROVIDER: S-EPMC6429155 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Facile Access to Fe(III)-Complexing Cyclic Hydroxamic Acids in a Three-Component Format.

Chupakhin Evgeny E Bakulina Olga O Dar'in Dmitry D Krasavin Mikhail M

Molecules (Basel, Switzerland) 20190228 5

Cyclic hydroxamic acids can be viewed as effective binders of soluble iron and can therefore be useful moieties for employing in compounds to treat iron overload disease. Alternatively, they are analogs of bacterial siderophores (iron-scavenging metabolites) and can find utility in designing antibiotic constructs for targeted delivery. An earlier described three-component variant of the Castagnoli-Cushman reaction of homophthalic acid (via in situ cyclodehydration to the respective anhydride) wa ...[more]

PMID: 30823493

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Project description:Whole-genome DNA microarray analysis of Geobacter sulfurreducens cells grown on Fe(III)-oxide or Mn(IV)-oxide versus cells grown on soluble Fe(III) citrate indicated that there were significant differences in transcription patterns during growth on the insoluble metal oxides compared to growth on soluble Fe(III). Many of the genes that appeared to be up-regulated during growth on the metal hydroxides were involved in electron transport. The most highly up-regulated genes for both conditions were omcS and omcT, which encode co-transcribed c-type cytochromes exposed on the outer surface of the cell that are known to be required for Fe(III) and Mn(IV)-oxide reduction. Other electron transport genes that were up-regulated on both insoluble metals included the gene coding for the outer membrane c-type cytochrome, OmcG, genes for the outer membrane proteins, OmpB and OmpC, and the gene that codes for the structural protein of electrically conductive pili, PilA. Genes that were up-regulated in cells grown on Fe(III)-oxide but not Mn(IV)-oxide, included outer membrane c-type cytochromes including OmcE, a putative DMSO reductase protein, and proteins from the cytochrome bc1 complex. Electron transport genes that were only up-regulated in Mn(IV)-oxide grown cells included the genes that code for the outer membrane c-type cytochromes, OmcZ and OmcB, the periplasmic c-type cytochrome, MacA, and fumarate reductase. Genetic studies indicated that the c-type cytochrome proteins, PpcH, OmcJ, OmcM, OmcV, MacA, OmcF, OmcI, and OmcQ, and the iron sulfur subunit of the cytochrome b/b6 complex, QcrA, are important for reduction of insoluble Fe(III)-oxides but do not appear to be important for Mn(IV) reduction. These results demonstrate that the physiology of Fe(III) reducing bacteria differ significantly during growth on insoluble electron and soluble electron acceptors and emphasizes the importance of c-type cytochromes in extracellular electron transfer in G. sulfurreducens. Geobacter sulfurreducens cells were grown with acetate (5 mM) provided as the electron donor and either Fe(III) oxide or Fe(III) citrate provided as the electron acceptor. Cells were harvested at mid-log and total RNA was extracted. Total RNA (0.5 μg) was amplified using the MessageAmp II-Bacteria Kit (Ambion, Foster City, CA) according to the manufacturers instructions. Ten micrograms of amplified RNA (aRNA) was chemically labeled with Cy3 (for the control or soluble electron acceptor condition) or Cy5 (for the experimental or insoluble electron acceptor condition) dye using the MicroMax ASAP RNA Labeling Kit (Perkin Elmer, Wellesley, MA) according to the manufacturer’s instructions.

Project description:Whole-genome DNA microarray analysis of Geobacter sulfurreducens cells grown on Fe(III)-oxide or Mn(IV)-oxide versus cells grown on soluble Fe(III) citrate indicated that there were significant differences in transcription patterns during growth on the insoluble metal oxides compared to growth on soluble Fe(III). Many of the genes that appeared to be up-regulated during growth on the metal hydroxides were involved in electron transport. The most highly up-regulated genes for both conditions were omcS and omcT, which encode co-transcribed c-type cytochromes exposed on the outer surface of the cell that are known to be required for Fe(III) and Mn(IV)-oxide reduction. Other electron transport genes that were up-regulated on both insoluble metals included the gene coding for the outer membrane c-type cytochrome, OmcG, genes for the outer membrane proteins, OmpB and OmpC, and the gene that codes for the structural protein of electrically conductive pili, PilA. Genes that were up-regulated in cells grown on Fe(III)-oxide but not Mn(IV)-oxide, included outer membrane c-type cytochromes including OmcE, a putative DMSO reductase protein, and proteins from the cytochrome bc1 complex. Electron transport genes that were only up-regulated in Mn(IV)-oxide grown cells included the genes that code for the outer membrane c-type cytochromes, OmcZ and OmcB, the periplasmic c-type cytochrome, MacA, and fumarate reductase. Genetic studies indicated that the c-type cytochrome proteins, PpcH, OmcJ, OmcM, OmcV, MacA, OmcF, OmcI, and OmcQ, and the iron sulfur subunit of the cytochrome b/b6 complex, QcrA, are important for reduction of insoluble Fe(III)-oxides but do not appear to be important for Mn(IV) reduction. These results demonstrate that the physiology of Fe(III) reducing bacteria differ significantly during growth on insoluble electron and soluble electron acceptors and emphasizes the importance of c-type cytochromes in extracellular electron transfer in G. sulfurreducens. Geobacter sulfurreducens cells were grown with acetate (5 mM) provided as the electron donor and either Fe(III) oxide or Fe(III) citrate provided as the electron acceptor. Cells were harvested at mid-log and total RNA was extracted. Total RNA (0.5 M-NM-<g) was amplified using the MessageAmp II-Bacteria Kit (Ambion, Foster City, CA) according to the manufacturers instructions. Ten micrograms of amplified RNA (aRNA) was chemically labeled with Cy3 (for the control or soluble electron acceptor condition) or Cy5 (for the experimental or insoluble electron acceptor condition) dye using the MicroMax ASAP RNA Labeling Kit (Perkin Elmer, Wellesley, MA) according to the manufacturerM-bM-^@M-^Ys instructions. RNA samples from three biological replicates were hybridized in duplicate on 12K Combimatrix antisense-detecting arrays. The experimental condition (DL1 grown with Fe(III) oxide as acceptor) was labeled with cy5, the control condition (DL1 grown with Fe(III) citrate as acceptor) was labeled with cy3

Dataset Information

Facile Access to Fe(III)-Complexing Cyclic Hydroxamic Acids in a Three-Component Format.

Publications

Facile Access to Fe(III)-Complexing Cyclic Hydroxamic Acids in a Three-Component Format.

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