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

Abstract

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.

Dithiocarbamate-based linear versus macrocyclic architecture: comparative studies and applications in protein interaction and heavy metal removal

“…[3][4][5] Recently, a comparative study of macrocyclic and acyclic picolinate derivatives for interaction with copper ions was carried out, and both compounds acted distinctively upon chelation with the metal. 6 Similar changes were observed with protein interaction studies, in which a high-level fold difference in the half-maximal inhibitory concentration (IC 50 ) between linear and cyclic analogues was exhibited. 7,8 These state-of-the-art research outcomes provide hints that molecules act differently towards proteins and metals upon change in their architecture.…”

Effect of the type of N-substituent in the benzo-18-azacrown-6 compound on copper(ii) chelation: complexation, radiolabeling, stability in vitro, and biodistribution in vivo

“…Moreover, the latter was more stable than a similar copper complex with a tripicolinate derivative of 18-azacrown-6, which released about 20% of the copper within 2 hours and was much more stable than the dipicolinate derivative of 15-azacrown-5 in the same excess of serum. 28 Taking into account a similar "out-cage" coordination with tripicolinate 18-azacrown-6, it can be concluded that coordination 1 (Fig. 7), specifically, in CuBATPic 2− induces the strongest chelation of Cu 2+ .…”

“…Such an out-cage coordination has previously been shown for other 18-azacrown-6 derivatives. 26,28 These complexes indicate that, in the case of small cations, the large macrocyclic cavity does not implement a macrocyclic effect, but mainly plays a restricting role in flexible backbones with donor pendant arms.…”

“…21 In contrast to the ligands mentioned above for copper chelation, 22–25 18-membered azacrown ethers bearing different pendant arms demonstrated out-cage coordination of small cations, including copper. 26–28 However, despite the absence of inclusion of cations into the macrocyclic cavity they demonstrate high in vitro stability of the 64 Cu labeled chelate. 28 Thus, large macrocycles provide fast complexation and some degree of rigidity, apparently impacting the stability of formed complexes.…”

Novel Hybrid Benzoazacrown Ligand as a Chelator for Copper and Lead Cations: What Difference Does Pyridine Make

“…Given the growing importance of nuclear medicine and the extending abilities of obtaining medically relevant radiometals, the design of functional polyazamacrocyclic ligands able to coordinate cations with suitable features has been attracting increased attention during the last decade. In the frame of systematic variation and the search for the best matching pairs between medical radiometals and chelators, we have synthesized those substituted with one type of arm and arm-free pyridine bisamide azacrown and benzoazacrown ethers [ 1 , 2 , 3 , 4 , 5 , 6 ]. We have shown that azacrown compounds with acetic arms are effective for binding bismuth [ 4 , 5 ], lead [ 7 ] and zinc [ 8 ] cations, regarding the nuclear medicine application of their radioisotopes.…”