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

Ye, Yunpeng; Liu, Min; Kao, Jeff; Marshall, Garland R.

doi:10.1002/bip.10471

Cited by 30 publications

(41 citation statements)

References 88 publications

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“…Previously, we synthesized a series of N,N ′‐dihydroxy peptides via fragment condensation of two protecting hydroxamate‐containing oligopeptides in solution using 9‐fluorenylmethoxycarbonyl/ tert ‐butyl (Fmoc/ tert ‐butyl) chemistry 20. Herein, we continued to apply this approach to the synthesis of the trihydroxamate peptides from a N‐benzyloxy‐phenylalanine building block that was prepared from D ‐3‐phenyllactic acid via its triflate intermediate in multiple synthetic steps 20. As summarized in Scheme , N‐benzyloxyphenylalanine ( 1) was reacted with H–Ala–OBu t in the presence of 1‐ethyl‐3‐(3‐dimethylaminopropyl)carbodiimide/1‐hydroxybenzotriazole (EDCI/HOBt) to give the dipeptide 2 .…”

Section: Resultsmentioning

confidence: 99%

“…As reported in the literature, ESI‐MS has provided a powerful tool for studying metal coordination under certain conditions. Previously, we have studied the metal‐binding properties of dihydroxamate‐containing peptides by multiple methods including ESI‐MS, ultraviolet‐visible (UV‐Vis) spectroscopy, high performance liquid chromatography (HPLC), and 1 H nuclear magnetic resonance (NMR)20 In particular, ESI‐MS was demonstrated to be an efficient, sensitive, accurate, repeatable, and powerful method for screening the relative metal‐binding properties of peptides of this type in limited amounts. The relative binding affinity and selectivity of dihydroxamate‐containing peptides were determined based on the rela tive abundance, which was calculated from the percentage of peaks related to a resulting metal complex such as singly charged species [LMH] + and doubly charged species [LMH 2 ] 2+ to the total ligand‐related peaks including [LH] + , [LNa] + , and [LH 2 ] 2+ , as well as [LMH] + and [LMH 2 ] 2+ , observed in an ESI‐MS spectrum.…”

Section: Resultsmentioning

confidence: 99%

“…Over the past decade, we12 and others3, 6, 13–18 have been interested in developing novel metal‐binding peptides. Our focus has primarily been on peptide‐bond modification to bind metals and preorganize the peptide backbone, leaving the side chains intact for molecular recognition 19, 20…”

Section: Introductionmentioning

confidence: 99%

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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: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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

Liu

Kao

et al. 2006

Biopolymers

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“…[7] Therefore, we focused on both Fe(III) and Ga(III) coordination. The tested solutions of DFO and Cypate-DFO were prepared by mixing 1.2 equivalent Fe(III) with the ligand (75µM, 1 equiv) in 50% aqueous acetonitrile and then swirled for two hours.…”

Section: Metal Coordination and Es-ms Analysismentioning

confidence: 99%

Synthesis, metal coordination, and cellular internalization of a siderophore-bearing NIR fluorescent carbocyanine probe

Xu²,

Bloch³

et al. 2006

SPIE Proceedings

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In order to explore novel NIR fluorescent probes for optical imaging in biomedicines, one desferrioxamine (DFO)-bearing NIR fluorescent probe was designed and synthesized based on a dicarboxylic acid-containing carbocyanine (Cypate). Similar to the free DFO, the resulting conjugate Cypate-DFO showed high binding affinity with Fe(III) and Ga(III) as identified by ES-MS. Nevertheless, the iron binding was found to quench its fluorescent emission significantly, suggesting that the siderophore moiety might perturb the spectroscopic properties of the attached carbocyanine fluorophore through metal binding. As observed by fluorescence microscopy, Cypate-DFO showed significant cellular internalization in A549 cells in vitro. Further studies on novel Cypate-DFO derivatives of this type may reveal some exciting properties and biological activities.

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“…This approach has been used to design selective agonists and/or antagonists and also to impart resistance to hydrolysis by the proteolytic enzymes [6]. Another strategy has been the preparation of N-hydroxyamides, which are good metal chelators and can impart conformational rigidity to the peptides [7]. Isosteric replacement of the scissile peptide bond represents another viable and popular approach in the rational design of peptidomimetics.…”

Section: Introductionmentioning

confidence: 99%

Geometry, transition states, and vibrational spectra of boron isostere of N‐methylacetamide by ab initio calculations

Malde

Khedkar

Coutinho

et al. 2005

Int J of Quantum Chemistry

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ABSTRACT:The basic unit of the peptide, the COONH bond, is responsible for imparting specific secondary structural features to peptides. Many modifications, such as isosteric/bioisosteric replacement of this basic unit, have been made to alter the properties of peptides. Isosteric replacement of the nitrogen atom by boron (boron peptides) is another plausible way of changing peptide characteristics. Like Nmethylacetamide (NMA), acetylmethylborane, or BMA, is a good model for studying boron peptides. The potential energy surface (PES) of BMA has been studied by Hartree-Fock (HF), density functional theory (DFT), and post-HF methods. The PES of BMA is an inverted form of the NMA hypersurface. Two minima and two saddle points of index 1 have been identified on this PES and fully optimized at the HF, Becke's three-parameter exchange functional and the gradient-corrected functional of Lee, Yang, and Paar, second-order Møller-Plesset (full), and quadratic configuration interaction method with single and double substitutions followed by a perturbative treatment of triple substitutions (QCISD) levels of theory. The minima correspond to structures with "omega" values close to 90°and 270°, and the transition states have omega values around 0°and 180°. The energy barrier for rotation around the "omega bond" is found to be 4.3 kcal/mol at the QCISD/6-31G* level, which is much lower than the 16 -23 kcal/mol barrier in NMA. The unique shape of the PES of BMA and the low barrier to rotation can be well explained by second-order orbital interaction studies. Normal-mode analysis reveals a significant shift in the BOH stretching frequency of BMA from that in alkyl boranes and borane-phosphine complexes. The replacement of nitrogen by boron bestows on such peptides greater proteolytic stability, more flexibility around the omega angle, and a unique preference for positive angles, all of which are absent in peptides of natural origin.

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

Cited by 30 publications

References 88 publications

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

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

Synthesis, metal coordination, and cellular internalization of a siderophore-bearing NIR fluorescent carbocyanine probe

Geometry, transition states, and vibrational spectra of boron isostere of N‐methylacetamide by ab initio calculations

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