Zinc and copper complexes with azacrown ethers and their comparative stability <i>in vitro</i> and <i>in vivo</i>

Aleshin, Gleb Yu.; Egorova, Bayirta V.; Priselkova, Anna B.; Zamurueva, Lyubov S.; Khabirova, Sofia Yurievna; Zubenko, Anastasia D.; Карноухова, Валентина А.; Федорова, О. А.; Kalmykov, Stepan N.

doi:10.1039/d0dt00645a

Cited by 11 publications

(18 citation statements)

References 35 publications

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“…The ligands H 3 BA3A and H 4 BATA were prepared as described earlier. [11,26] NMR study 1 H NMR spectra were recorded at 25°C on Varian Inova 400 spectrometers. Chemical shifts are reported in parts per million (δ) relative to the deuterated solvent used as the internal reference (D 2 O δ = 4.75).…”

Section: Synthesis Of Ligandsmentioning

confidence: 99%

Investigating the Bismuth Complexes with Benzoazacrown Tri‐ and Tetra‐Acetates

et al. 2021

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The complexation properties towards Bi 3 + of benzoazacrown ligands with five (H 3 BA3A) and six (H 4 BATA) heteroatoms and corresponding number of acetic arms have been investigated. Complexation constants were determined via potentiometric titration for BA3ABi complex (logβ = 26.2) and refined for BATABi complex (logβ = 31.7). According to NMR, X-ray and EXAFS results, chelation of cation by H 3 BA3A appears to be outside the macrocyclic cavity both in the solid state and in the aqueous solution. This out-cage location despite the high stability constant causes serum and in vivo instability of complex of smaller azacrown H 3 BA3A in contrast to H 4 BATA. Whereas the larger macrocycle and four pendant arms of H 4 BATA provide long-range coordination effectively shielding the cation thereby ensuring high inertness in vitro, low accumulation of the radionuclide in the organs, and fast clearance.

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Section: Synthesis Of Ligandsmentioning

confidence: 99%

Investigating the Bismuth Complexes with Benzoazacrown Tri‐ and Tetra‐Acetates

et al. 2021

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“…Under the same conditions in a similar way the protonation constants of this ligand were determined previously. [3] According to the obtained values: logβ(LHPb) = 21.0(1), logβ(LPb) = 17.2(1), logβ(LPbOH) = 23.1(1), logβ (LPb(OH) 2 ) = 26.3(1)at lower pH values a complex with a monoprotonated form of the ligand is formed, then it deprotonates to the LPb form, and at pH>8, LPb(OH) n hydroxide complexes are formed (Figure 1). Noteworthy that in opposite to the previously studied precursors of the ligand H 3 BA3A, [5] the formation of insoluble lead hydroxides was not observed in the entire studied pH range 2.5-11.…”

Section: Complexation In the Pb 2+ -H 3 Ba3a Systemmentioning

confidence: 99%

“…The proton resonances of H 3 BA3A at рD = 12.4 corresponded to the deprotonated form of the ligand (Figure 2) in accordance with the potentiometric data. [3] The area of aromatic protons in the 1 H NMR spectrum contains one multiplet corresponding to the protons of the benzene ring H 1 and H 2 . In the area of aliphatic protons four broadened singlets corresponding to the macrocyclic protons H 4 , H 5 , H 6 and H 7 , and two singlets of the CH 2 groups of acetate substituents (H 8 and H 10 ) are seen.…”

Section: Investigation Of Complex Formation Of H 3 Ba3amentioning

confidence: 99%

“…For comparison, the synthesis at a ligand concentration of 20 μM was carried out by heating up to 90 °C for 30 minutes; the reaction yield did not differ from that obtained at room temperature. Thus, it has been shown that H 3 BA3A binds lead cations, as well as copper and zinc cations, [3] rapidly and without additional heating. This fact can be explained due to the larger size of the macrocyclic cavity than that of the cyclene-based ligands, the chelation of which requires elevated temperatures (H 4 DOTA, DOTAM).…”

Section: Benzoazacrown Compound As a Chelator For Lead Cationsmentioning

confidence: 99%

“…[1,2] Recently, we have shown that triacetate of benzoazacrown ether H 3 BA3A can effectively bind cations of doublecharged cations Cu 2+ and Zn 2+ . [3] In this work, we attempted to evaluate from different points the potential of this ligand for therapeutic use with 212 Pb. On the other hand, in addition to the importance of binding the 212 Pb radionuclide for therapy, chelation of lead cations in general has been of medical interest for a long time from the point of detoxification of the body in case of poisoning with heavy metals, including lead.…”

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Triacetate of Benzoazacrown Compound as a Chelator for Lead Cations Promising for Targeted Radiopharmaceuticals

Egorova¹,

Zamurueva²,

Zubenko³

et al. 2021

MHC

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Triacetate of 15-benzoazacrown-5 compound (H 3 BA3A) is a new ligand that has shown advantages towards chelation of some cations. In this paper H 3 BA3A was consequently studied for binding of lead cation. With respect to nuclear properties of 212 Pb radioisotope it can be used for therapy of various oncological diseases mainly due to alpha-emitting daughter radionuclide 212 Bi. Complexes of such radionuclides are considered as parts of targeted radiopharmaceuticals that can be conjugated with biomolecules to provide address delivery to cancerous tissues. Medical radionuclides are commonly short-lived and biomolecules are often heat-sensitive. That is why fast and stable complexation of trace amounts of lead cations in biologically relevant media without additional heating higher than 37 °C is important and challenging task. At the beginning we determined complexation constants in wide pH range including different protonated and hydrolyzed complex species via potentiometric titration technique. The obtained values are high enough for lead chelates logβ(BA3APb -) = 17.2 (1). Structural features of complex in aqueous solution were established due to 1 H and 13 C NMR spectroscopy. High resolution of obtained spectra and comparison with spectrum of deprotonated ligand shows presence of one rigid conformer of complexed form in the aqueous solution with C s symmetry. In order to study labelled compounds we used longer lived isotope of lead 210 Pb isolated from solution of 226 Ra. Using thin layer chromatography and gamma-spectrometry it was found that 100 μM of ligand is enough to completely chelate 210 Pb in the tracer concentration related to radiopharmaceutical concentration of 212 Pb. According to pH speciation obtained in complexation constant determination, pH 5.5-6 was selected for labelling experiments. Noteworthy, the labeled compound was obtained within 1-5 minutes at room temperature as well as upon heating at 90 o C. Macrocyclic H 3 BA3A demonstrates fast complexation apparently due to larger crown cavity compared to cyclen cavity in H 4 DOTA. This was indirectly shown in potentiometric titration where waiting time for curve's points was no longer than 5 minutes indicating that equilibrium was achieved within 5 minutes. In order to evaluate possible trans-chelation and transmetallation of complex in living organism we performed challenging experiments in static conditions: in presence of nine-fold excess of serum proteins, biologically relevant cations 5 mM Ca 2+ , 5 mM Mg 2+ , 0.1 mM Zn 2+ , 0.1 mM Cu 2+ , 0.1 mM Fe 3+ and isotonic solution of 0.15 M NaCl. It was shown that the 100 % intactness of complex can be kept for up to two days of incubation in competing media. Summarizing, the H 3 BA3A forms highly stable complex with lead cation not only in model solution, but also in presence of challenging agents. This stability is provided by high stability constants and rigid structure in solution.

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Comparative Study of Macrocyclic and Acyclic Picolinate Derivatives for Chelation of Copper Cations

et al. 2021

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In this work we presented a synthesis and investigation of relative acyclic and macrocyclic polyamines with picolinate pendant arms as potential chelators for copper radiopharmaceuticals. It has been shown that linear chelators lacking bisamide moiety are much more basic and form complexes with higher stability constants compared to macrocyclic ones. Both types of ligands possess many donor sites due to picolinate groups enabling formation of polynuclear complexes in the solution and solid state. According to crystal structures metal cations coordinates with studied ligands through the binding with aminogroups and picolinates donor atoms, while terminal aminogroups of acyclic ligands do not take part in the complex formation. Tripicolinate azacrown ligand coordinates cations outside the macrocyclic cavity in non-equivalent positions. However this out-cage location as well as a moderate logK value do not induce fast release of cation from this complex in the challenging medium of serum proteins.

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Zinc and copper complexes with azacrown ethers and their comparative stability in vitro and in vivo

Abstract: Radiolabeled macrocyclic zinc complexes are more stable in serum than analogous copper compounds; an azacrown-derived cycle with five heteroatoms coordinates zinc, providing fast complexation and high in vivo stability.

Cited by 11 publications

References 35 publications

Investigating the Bismuth Complexes with Benzoazacrown Tri‐ and Tetra‐Acetates

Investigating the Bismuth Complexes with Benzoazacrown Tri‐ and Tetra‐Acetates

Triacetate of Benzoazacrown Compound as a Chelator for Lead Cations Promising for Targeted Radiopharmaceuticals

Comparative Study of Macrocyclic and Acyclic Picolinate Derivatives for Chelation of Copper Cations

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