Synthesis, characterization, and theranostic applications of pyridine containing macrocyclic ligands and their divalent transition metal complexes

Abstract

Pyridine containing aza-macrocyclic ligands represent a broad and still emerging family of compounds that can be utilized for various applications. These include their use as diagnostic/therapeutic agents, catalyst, and biomimetic models. This work presents the syntheses of three rigidified macrocycles along with the detailed characterization of their transition metal complexes. The inclusion of a second aromatic ring into the backbone of 2.8 led to a formation of a surprisingly flat Mn(II) complex, which increased the longitudinal relaxivity of the chelate compared to its parent molecule, due to the open axial positions around the seven-coordinate metal center. The study of the two piperazine containing macrocycles (3.2 and 3.4) revealed that the configurational effects can lead to [1+1] or [2+2] cyclocondensations depending on the length of the carbon linker in the a,¿-diamino building blocks. Additionally, three pyridine containing 12-membered tetra-aza macrocycles have been introduced as potential therapeutics for neurodegenerative diseases. These represent the third generation of antioxidant molecules in the Green Group: a combination of bioinspired small molecules with the radical scavenger hydroxylated pyclen (4.3). The O-functionalized 4.25 showed increased activity in the utilized antioxidant assay. Also, the asymmetric 4.36 retained 4.3’s transition metal binding affinity. The investigation of the 8-hydroxyquinoline linked 4.3, 5.9 evidenced a significant increase in its metal complex stabilities, with a clear preference for Zn(II). At the same time, the Cu(II) complex showed a pH-dependent color change close to physiological pH, which can be attributed to the protonation of the phenolic OH group on the pendant arm. Finally, a comprehensive analysis of ten 12-membered aza-macrocyclic ligand showed the result of substituting the 4-position of the pyridine ring. While electron donating groups do not have a significant effect on the acid-base equilibria, electron withdrawing groups lowered both the total basicity of the pyclen analogues as well as the protonation constant associated with the pyridine nitrogen. This same trend was observed in case of the stability constants of complexes formed with divalent transition metal ions. Also, the N-methylation of 4.2 and 4.3 parent compounds led to results revealing lower total basicity and metal binding constants for 6.7 and 6.8.