Tripodal Peptide Hydroxamates as Siderophore Models. Iron(III) Binding with Ligands Containing H-(Alanyl)n-β-(N-hydroxy)alanyl Strands (n = 1−3) Anchored by Nitrilotriacetic Acid

Hara, Yukihiro; Shen, Langtao; Tsubouchi, and Akira; Akiyama, Masayasu; Umemoto, Kimiko

doi:10.1021/ic0001210

Cited by 29 publications

(22 citation statements)

References 50 publications

(70 reference statements)

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“…The continued use of DFO , despite its lack of oral bioavailability and difficulties in patient compliance, strongly suggested it as a lead compound for developing novel metal‐binding peptides with improved oral bioavailability and more selective activities. Early efforts to explore DFO and other siderophore analogs were reported by the Akiyama,34–38 the Bergeron,39–41 the Miller,42, 43 and the Raymond44–46 groups. More recently, we also designed and synthesized trihydroxamate‐containing analogs of DFO 12, 47–49 and other siderophore analogs as potential oral therapeutics for iron‐overload diseases.…”

Section: Introductionmentioning

confidence: 99%

Novel trihydroxamate‐containing peptides: Design, synthesis, and metal coordination

Liu

Kao

et al. 2006

Biopolymers

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Novel trihydroxamate-containing peptides were designed to mimic desferrioxamine (Desferal(R), DFO, a naturally occurring siderophore) but possess distinct conformational restrictions and varied lipophilicity to probe structure vs. metal coordination. The synthesis was performed via fragment condensation of hydroxamate-containing oligopeptides such as Fmoc-Leu- Psi[CON(OBz)]-Phe-Ala-Pro-OH and H-Leu-Psi[CON(OBz)]-Phe-Ala-Pro-OBu(t) (Fmoc: 9-fluor enylmethoxycarbonyl; OBz: benzyl; OBu(t): tert-butyl) either in solution or on a solid support. The metal-binding properties were studied by electrospray ionization-mass spectroscopy (ESI-MS), ultraviolet (UV)-visible spectroscopy, and (1)H nuclear magnetic resonance (NMR). Similar to the dihydroxamate analogs previously explored [Biopolymers (Peptide Science), 2003, Vol. 71, pp. 489-515], the compounds with three hydroxamates arrayed at 10-atom intervals, i.e., H-[Leu-Psi[CON(OH)]-Phe-Ala-Pro](3)-OH (P1), cyclo[Leu-Psi[CON(OH)]-Phe-Ala-Pro](3) (P2), and H-[Leu-Psi(CONOH)-Phe-Ala-Pro](2)-Leu-NHOH (P7), exhibited high affinities for intramolecular coordination with Fe(III) and Ga(III). As expected, both P1 and P2 showed higher relative Fe(III)-binding affinities than the corresponding dihydroxamate-containing peptide analogs (P11 and P12). Even though both P1 and P2 did not compete with DFO in the relative metal-binding affinity in both solution and gas phases, P1, P2, and DFO exhibited similar relative binding selectivities to 11 different metal ions including Fe(III), Fe(II), Al(III), Ga(III), In(III), Zn(II), Cu(II), Co(II), Ni(II), Gd(III), and Mn(II). Compared to the other metal ions, they had higher relative binding affinities with Fe(III), Fe(II), Al(III), Ga(III), and In(III). The decreased metal-binding affinities of P1 and P2 in comparison with DFO suggested the conformational restrictions of their backbones perturb their three hydroxamate groups from optimal hexadentate orientations for metal coordination. As detected by ESI-MS, P2 was distinguished from both P1 and DFO by solvation of its Ga(III) and Fe(III) complexes (such as acetonitrile or water), thereby stabilizing the resulting complexes in the gas phase. Noteworthy, P2 led to 69% death rate in Hela cells at a concentration of 50 microM, exhibiting higher cytotoxicity than DFO in vitro despite its much lower affinity for iron. This enhanced toxicity may simply reflect the increased lipophilicity of the cyclic trihydroxamate (P2) together with the improvements in its cell penetration, and/or subsequent intracellular molecular recognition of both side chains and hydroxamate groups. The cytotoxicity was significantly suppressed by precoordination with Ga(III) or Fe(III), suggesting a mechanism of toxicity via sequestration of essential metal ions as well as the importance of curbing the metal coordination before targeting. The potential of such siderophore-mimicking peptides in oncology needs further exploration.

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Section: Introductionmentioning

confidence: 99%

Novel trihydroxamate‐containing peptides: Design, synthesis, and metal coordination

Liu

Kao

et al. 2006

Biopolymers

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“…These compounds are capable of the inhibition of a variety of enzymes, including ureases [3][4][5], peroxidases [6], and matrix metalloproteinases [7,8]. They are also capable of competing as siderophores for iron-(III) [9][10][11]. In the biomedical sciences, hydroxamic acids moieties are used in the design of therapeutics targeting cancer [12][13][14][15], cardiovascular diseases [16,17], HIV [18,19], Alzheimer's [20,21], malaria [22][23][24][25][26][27], allergic diseases [28][29][30], tuberculosis [31][32][33][34][35][36], metal poisoning [37][38][39][40], and ironoverload [41][42][43].…”

Section: Introductionmentioning

confidence: 99%

Hydroxamic Acids as Pharmacological Agents

Muri¹,

Nieto²,

Sindelar³

et al. 2002

CMC

232

149

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A variety of hydroxamic acid derivatives have recently been touted for their potential use as inhibitors of hypertension, tumor growth, inflammation, infectious agents, asthma, arthritis, and more. Here we provide a comprehensive review of the basic medicinal chemistry and pharmacology of hydroxamic acid derivatives that have been examined as inhibitors of zinc metalloproteases, matrix metalloproteinases, leukotriene A(4) hydrolases, ureases, lipoxigenases, cyclooxygenases, as well as peptide deformilases.

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“…41,42 More recent studies 43,44 by Hara et al have focused on iron complexation by oligomers of Ala-Ala-⌿[CO-NOH]-␤-Ala. In contrast, we initially focused on N,NЈ-dihydroxypeptides.…”

Section: Introductionmentioning

confidence: 99%

Peptide‐bond modification for metal coordination: Peptides containing two hydroxamate groups

Liu

Kao

et al. 2003

Biopolymers

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Peptide-bond modification via N-hydroxylation has been explored as a strategy for metal coordination to induce conformational rigidity and orient side chains for specific molecular recognition. N-Hydroxyamides were prepared by reacting N-benzyloxyamino acid esters or amides with Fmoc-AA-Cl/AgCN (Fmoc: 9-fluorenylmethoxycarbonyl; AA: amino acid) in toluene or Fmoc-AA/HATU/DIEA in DMF (HATU: O-(7-azabenzotriazol-lyl)-1,1,3,3-tetramethyluronium hexafluorophosphate; DIEA: N,N-diisopropylethylamine; DMF: N,N-dimethylformamide), followed by deblocking of benzyl protecting groups. Novel linear and cyclic N,N'-dihydroxypeptides were efficiently assembled using Fmoc chemistry in solution and/or on a solid support. As screened by electrospray ionization-mass spectroscopy (ESI-MS), high iron-binding selectivity and affinity were attainable. Compounds having a spacer of two alpha-amino acids between the amino acids bearing the two hydroxamates, i.e., a spacer of 8 atoms, generated 1:1 iron complex species in the gas phase. Moreover, high performance liquid chromatography (HPLC), uv/vis, and (1)H-NMR analyses provided direct evidence for complex formations in solution. Significantly, the representative compound cyclo(Leu-Psi[CON(OH)]-Phe-Ala-Pro)(2) (P8) may serve as a robust metal-binding scaffold in construction of a metal-binding library for versatile metal-mediated molecular recognition.

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Tripodal Peptide Hydroxamates as Siderophore Models. Iron(III) Binding with Ligands Containing H-(Alanyl)_n-β-(N-hydroxy)alanyl Strands (n = 1−3) Anchored by Nitrilotriacetic Acid

Cited by 29 publications

References 50 publications

Novel trihydroxamate‐containing peptides: Design, synthesis, and metal coordination

Novel trihydroxamate‐containing peptides: Design, synthesis, and metal coordination

Hydroxamic Acids as Pharmacological Agents

Peptide‐bond modification for metal coordination: Peptides containing two hydroxamate groups

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