Advances in the Chemical Biology of Desferrioxamine B

Codd, Rachel; Richardson-Sanchez, Tomas; Telfer, Thomas J.; Gotsbacher, Michael P.

doi:10.1021/acschembio.7b00851

Cited by 75 publications

(61 citation statements)

References 164 publications

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“…The exquisite affinity of 1 for Fe III (log K a =31) supports its use either as a single agent, or more often in combination therapy, for secondary iron overload disease in people with transfusion‐dependent blood disorders . The solvent‐exposed primary amine group in 1 is not involved in Fe III coordination and is amenable to labeling, as demonstrated by the production of a range of derivatives by means of semisynthetic chemistry …”

Section: Introductionmentioning

confidence: 99%

Azido‐Desferrioxamine Siderophores as Functional Click‐Chemistry Probes Generated in Culture upon Adding a Diazo‐Transfer Reagent

Gotsbacher

Codd

2020

ChemBioChem

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Scheme1.Structures of DFOB (1), azido-DFOB( 2), DFON 1 ,DFOA 1-3 ,a nd membersoffour classes of PDB substrates used to augment culturesofS. pilosus. ( 1), together with its observed MS 2 fragmentationpattern, B) DFOA-constitutional isomers 3-9,g enerated by usingP DB with DB as substrate, and the corresponding azido analogues 10-16,a nd C) putative dimeric and monomeric compounds that could be generated by using PDB with 5APAa ssubstrate. Scheme2.Structures of:A)DFOB

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Section: Introductionmentioning

confidence: 99%

Azido‐Desferrioxamine Siderophores as Functional Click‐Chemistry Probes Generated in Culture upon Adding a Diazo‐Transfer Reagent

Gotsbacher

Codd

2020

ChemBioChem

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“…5) is produced by V. cholerae (98). An extensive review of polyamine-containing siderophores and other natural products is not possible in this minireview, but it is worth mentioning the analytical chemical and biochemical tour de force by Codd et al (99,100) that revealed the biosynthetic sequence of the linear and cyclic diamine-based desferrioxamine-type siderophores.…”

Section: Polyamine-based Siderophoresmentioning

confidence: 99%

Polyamine function in archaea and bacteria

Michael

2018

Journal of Biological Chemistry

139

130

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Most of the phylogenetic diversity of life is found in bacteria and archaea, and is reflected in the diverse metabolism and functions of bacterial and archaeal polyamines. The polyamine spermidine was probably present in the last universal common ancestor, and polyamines are known to be necessary for critical physiological functions in bacteria, such as growth, biofilm formation, and other surface behaviors, and production of natural products, such as siderophores. There is also phylogenetic diversity of function, indicated by the role of polyamines in planktonic growth of different species, ranging from absolutely essential to entirely dispensable. However, the cellular molecular mechanisms responsible for polyamine function in bacterial growth are almost entirely unknown. In contrast, the molecular mechanisms of essential polyamine functions in archaea are better understood: covalent modification by polyamines of translation factor aIF5A and the agmatine modification of tRNA Ile . As with bacterial hyperthermophiles, archaeal thermophiles require long-chain and branched polyamines for growth at high temperatures. For bacterial species in which polyamines are essential for growth, it is still unknown whether the molecular mechanisms underpinning polyamine function involve covalent or noncovalent interactions. Understanding the cellular molecular mechanisms of polyamine function in bacterial growth and physiology remains one of the great challenges for future polyamine research. Figure 4. Polyamine dependence of biofilm formation in B. subtilis. WT, B. subtilis NCIB3610; ⌬speA, deletion mutant of arginine decarboxylase; Spd, spermidine; Nspd, norspermidine. Complex colony biofilms were grown on solid MSgg medium. Adapted from Hobley et al. (86).

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“…Pharmaceutics 2020, 12, x FOR PEER REVIEW 5 of 13 The 8-arm-PEG-DFO conjugates were synthesized by coupling DFO to an 8-arm-PEG with a mean molecular weight of 20 kDa or 40 kDa, respectively ( Figure 1). 1 HNMR was used to ensure the synthesis of the 8-arm-PEG-DFO conjugates (Figure 2A). In the spectrums of conjugates, the newlyappeared conjugate peak at 7.75 ppm was assigned to the amido bonds, indicating the conjugation of DFO to the 8-arm-PEG macromolecules.…”

Section: The Synthesis and Characterization Of 8-arm-peg-dfo Conjugatesmentioning

confidence: 99%

“…Chelation therapy has been widely used in the treatment of iron overload, especially when the patients received a regular blood transfusion, such as for thalassemia [1,2]. Blood transfusion adds to the iron burden in patients with high risk of the damage of the liver, endocrine system, and heart.…”

Section: Introductionmentioning

confidence: 99%

A Novel Star Like Eight-Arm Polyethylene Glycol-Deferoxamine Conjugate for Iron Overload Therapy

Yang

Liu

et al. 2020

Pharmaceutics

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The traditional iron chelator deferoxamine (DFO) has been widely used in the treatment of iron overload disease. However, DFO has congenital disadvantages, including a very short circular time and non-negligible toxicity. Herein, we designed a novel multi-arm conjugate for prolonging DFO duration in vivo and reducing cytotoxicity. The star-like 8-arm-polyethylene glycol (8-arm-PEG) was used as the macromolecular scaffold, and DFO molecules were bound to the terminals of the PEG branches via amide bonds. The conjugates displayed comparable iron binding ability to the free DFO. Furthermore, these macromolecule conjugates could significantly reduce the cytotoxicity of the free DFO, and showed satisfactory iron clearance capability in the iron overloaded macrophage RAW 246.7. The plasma half-life of the 8-arm-PEG-DFO conjugate was about 190 times than that of DFO when applied to an intravenously administered rat model. In conclusion, research indicated that these star-like PEG-based conjugates could be promising candidates as long circulating, less toxic iron chelators.Pharmaceutics 2020, 12, 329 2 of 13 pharmacokinetics (PK) of DFO was thus regarded as a promising approach to promote therapeutic efficacy and mitigate the side effects.Many attempts have been conducted by conjugating DFO to a water-soluble polymer to improve its PK properties. For example, the hyper-branched glycerol was used to form conjugates with DFO, which made it possible to chelate iron efficiently and prolong the circulation time of API in the blood [7,15,16]. Specially, the circulation half-life (t 1/2 ) of DFO was increased by up to 44 h in mice, a 484-fold increase compared to native DFO. Nevertheless, it has not yet been pursued in clinical study, probably due to the limitations of the excipients and cumbersome synthesis methods. Other DFO macromolecular conjugates, such as polyrotaxane-DFO and dextran-DFO conjugate, also showed efficacies in iron chelation and rather low cell toxicities [17,18]. However, the reported t 1/2 was prolonged to be a moderate level (~1 h). The PEG has been used in the many products since it was approved by the FDA as a pharmaceutical polymer material [19][20][21]. The PEGylation conjugates provide a solution to increase the stability of drugs and prolong their blood circulation. Tremendous efforts have been devoted to create PEG-based solutions for improving the defect of the DFO. In previous studies, the DFO was conjugated to the copolymer with the PEG side chain or the PEG based three-arm macromolecule, for designing the biocompatible, long-circulating macromolecule iron-chelator [22,23]. These polymer conjugates, however, suffered from the wide molecular range and low loading efficacy of API, making the following translations difficult. Recently, multi-armed PEGs have gained much attention in both academic and industrial fields, due to their superiority in drug-loading efficacies compared to the traditional linear PEG [24][25][26]. Herein, we successfully synthesized and designed an 8-arm-polyethylene glycol-...

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Advances in the Chemical Biology of Desferrioxamine B

Cited by 75 publications

References 164 publications

Azido‐Desferrioxamine Siderophores as Functional Click‐Chemistry Probes Generated in Culture upon Adding a Diazo‐Transfer Reagent

Azido‐Desferrioxamine Siderophores as Functional Click‐Chemistry Probes Generated in Culture upon Adding a Diazo‐Transfer Reagent

Polyamine function in archaea and bacteria

A Novel Star Like Eight-Arm Polyethylene Glycol-Deferoxamine Conjugate for Iron Overload Therapy

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