Hemiporphyrazines: Synthesis, Photophysical Properties and Reactivity

Abstract

DNA quadruplex structures are attracting great scientific interest because of increasing evidence that these structures play important roles in biological processes ranging from replication, transcription, and recombination to telomere integrity. The use of small molecules to selectively target these structures in vivo is emerging as a promising way to interfere with telomere replication in tumor cells and provides potential anticancer agents. A large number of quadruplex binding ligands have already been reported. In general, they selectively interact with terminal GGGG-tetrads via π-π stacking interactions. However, in addition to GGGG-tetrads, GCGC-tetrads are known to be involved in quadruplex formation in vitro. Even though these so-called “mixed tetrads” might also have biological relevance, selective GCGC-tetrad binding probes have not yet been reported. Hemiporphyrazines (Hps) are non-aromatic, 20 π-electron phthalocyanine (Pc) derivatives that consist of two co-facial pyridine rings and two co-facial isoindole units linked through four aza bridges. Due to their planarity, extended π-conjugation, and C2-type symmetry, they are good candidates for selectively targeting GCGC-tetrads. Unsubstituted Hps are, however, notoriously insoluble materials and therefore little is known about their chemical and photophysical properties. As a consequence, this Master thesis is focused on the synthesis, structure, photophysical and reactivity properties of Hps to assess their potential as future GCGC-tetrad binding ligands. Free-base hemiporphyrazine (HpH2) was synthesized and its structure was analyzed by single crystal X-ray diffraction. HpH2 adopts a nearly planar structure and its macrocyclic core contains alternating double and single bonds. This is consistent with the non-aromatic character of these compounds. Furthermore, HpH2 has a very high water affinity and readily absorbs water from the atmosphere to form a yellow monohydrate (HpH2·H2O). This compound has a saddle-shaped conformation and distinct photophysical properties. The use of bulky metal triflates (M(OTf)2) as sources of metal ions during macrocyclization furnished metallo Hps (MHps) with enhanced solubility properties. Octahedral zinc and nickel trans-ditriflate hemiporphyrazine complexes “HpH2Zn(OTf)2” and “HpH2Ni(OTf)2” provide two such examples.