Biomedical and Biochemical Applications of Self-Assembled Metallacycles and Metallacages

Abstract

Conspectus Coordination-driven self-assembly utilizes the spontaneous formation of metal-ligand bonds in solution to drive mixtures of molecular building blocks to single, unique 2D metallacycles or 3D metallacages based on the directionality of the precursors used. The supramolecular coordination complexes (SCCs) obtained via this process are characterized by well-defined internal cavities and facile pre- or post-self-assembly functionalizations. These properties augment the modularity of the directional bonding design strategy to afford structures with unprecedented tunability both spatially and electronically. Over the past decades, a number of synthetic design methodologies have become established which has led to a substantial library of complexes supported by numerous structural studies. More recently, there has been an emergence of research centered on the potential applications of SCCs, which has developed rapidly on the foundations provided by the aforementioned synthetic and structural bodies of work. The necessary presence of metal ions as structural elements for the directional bonding approach can be exploited to provide biological activity to an SCC, particularly for Pt and Ru-based structures. Since these two metals are not only among the most commonly used for coordination-driven self-assembly but are also the basis for a number of small molecule anticancer agents, a growing number of SCCs have been evaluated for their antitumor properties. When the internal cavity of a cage is optimized for guest encapsulation, a second vector for biological activity, namely drug delivery, is unlocked. Since cages can offer both inherent activity due to their metal ions, as well as delivery of exogenous drug molecules, such ensembles are particularly promising chemotherapeutic agents. The non-covalent interactions of SCCs with guest molecules oftentimes manifest photophysical changes to the resulting host/guest complex. Since a metallacage or cycle can be readily tuned to match a specific guest, certain SCCs are well-suited to act as fluorescence-based sensors for biologically relevant analytes. These interactions are not limited to small molecule analytes, however, and SCCs are increasingly being studied for their chemistry with macro biomolecules including DNA and proteins. In particular, dinuclear iron and ruthenium-based helicates bind to a variety of DNA constructs through non-covalent mechanisms. Studies concerning these cylindrical SCCs, which have expanded beyond Ru and Fe, often include characterizations of specific interactions with DNA or other biomolecules. Such investigations are not limited to dinuclear M2L3 helicates; Pt-based squares are well-suited to stabilize G-quadruplex DNA and rhomboid metallacycles can unravel supercoiled DNA, further demonstrating the versatility of multinuclear supramolecular architectures. Understanding these interactions in the context of observed cytotoxicities and other biological consequences is critical for developing new chemotherapeutic agents and developing mech...

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