Nickel, copper, and iron complexes of aminopyridine macrocycles with a modifiable pendant aminopropyl arm

It is known that the oxygen activation at the metal center in iron bleomycin (Fe-BLM) is the key step in single- and double-strand sequence-specific DNA cleavage, which is considered to be responsible for the anti-cancer activity of the drug. The rich redox chemistry of Fe-BLM related to its anti-cancer activity has inspired studies on bleomycin models and analogs. From these studies it has been found that the presence of a pyrimidine or pyridine ring is essential for oxygen activation by iron-bleomycin mimics. However, while the design of small synthetic active-site analogs can be used to obtain information about fundamental aspects of structure, reactivity and mechanism the modeling of the non-symmetric iron coordination sphere in Fe-Blm while seemingly simple, represents a significant challenge. One means by which this problem can be overcome is in the design of polydentate ligands, in which the donor atoms mimic the iron environment. It is in the design of a ligand framework capable of reproducing the metal coordination sphere of iron bleomycin that the primary concern for our research lays.; Template Schiff base condensations between dicarbonyl compounds and diamines are among the simplest and most popular methods for the synthesis of macrocycles. The nature of the metal template used determines the outcome of Schiff base condensation between a difunctional carbonyl component (2,6-diacetyl and 2,6-diformylpyridine) and a trifunctional amine component (tris-(3-aminopropylamine), trpn). It was thought that the coordination requirements imposed by a pentadentate ligands bearing a fifth donor atom in the pendant arm would be even more severe than those of a more simple tetradentate macrocycles, and that the placement of a fifth donor would facilitate the formation of non-symmetric condensation products in the template reactions. In addition the use of a primary amine would potentially allow for the reversible interconversion of our complexes between tetra and pentadentate by the simple protonation/deprotonation of the amino group on the arm using acid or base once the complexes had been made. Both Cu(II) and Ni(II) facilitate [1+1] condensation with the formation of macrocyclic products.; Herein we report a series of macrocyclic Ni(II) and Cu(II) complexes that were prepared by the template [1+1] condensation of a 2,6-disubstituted pyridine (2,6-diacetyl- or 2,6-diformylpyridine) and tris-(3-aminopropyl)amine. The Ni(II) complexes were further modified by the reduction of the azomethine bonds with sodium borohydride. (Abstract shortened by UMI.)...