The Green research group focuses on applications at the interface of chemistry and biology. The areas of interest include coordination chemistry of relevance to:

These projects have aspects that are appropriate for both graduate and undergraduate students interested in the broad fields of bioinorganic and analytical chemistry and will serve as an excellent learning platform for students to develop the fundamental research skills and critical thinking needed to perform quality research.

The Green Research Group has developed a new family of N-Heterocyclic amines containing a tunable pyridine core. This system has multiple applications in the fields of therapeutics, imaging, and catalysis. We are currently exploring applications in all of these areas. Our recent studies are detailed below. Please check back frequently for updates on our progress!

Ligand Development

**Lincoln, K. M.; *Offutt, M.; *Hayden, T.; *Saunders, R.; Green, K. N., “The Structural, Spectral and Electrochemical Properties of Ni(II), Cu(II) and Zn(II) Complexes Containing 12-membered Pyridol-based Tetra-aza Macrocycles", Inorg. Chem.  2014, 53, 1406-1416. DOI:10.1039/C2CC36808K.

1    2

The synthesis, characterization and spectroscopy of Ni(II), Cu(II) and Zn(II) complexes derived from L1-L3 are examined. The aim of this work was to understand how the electronic nature of the metal center is altered by a subtle change in the structure of the pyridine ring and in particular to determine if the hydroxyl group acts as an electron-donating or electron-withdrawing substituent, with respect to the metal center. This type of information is useful because it provides fundamental insight into how m- and p-hydroxylation of the pyridine ring modifies the electronic nature of the π-system and why this subtle change affects the electronic behavior of the metal center. The data from our recent work led to the conclusion that introduction of the hydroxyl substituent increased the amount of negative charge density throughout the pyridine ring. Overall, the results of this study revealed that the Lewis-basicity of the 12-membered pyridine- and pyridol-based tetra-aza macrocyclic ligands increases across the series L2 > L1 >L3.


Therapeutics for Neurodegenerative Disorders

The current therapeutics for neurodegenerative disorders do provide symptom relief but do not mitigate the source of the damage. Therefore, there is an immediate need to develop molecules that can cross the BBB and serve as antioxidant components to halt the oxidative damage that results in damage to neurons. The pyridine/pyridol backbone has long been known to possess antioxidant capacity and used ubiquitously by nature (tannins) for these purposes. Pyridine and pyridole moieties can quench multiple ROS species, with the former being able to isolate oxygen containing molecules and the later also being able to serve as a radical scavenger. We have synthetically combined this later structural component (pyridol) with amine ligands having affinity for metal-ions known to cause ROS. The amine binding strategy shifts the redox potentials of the metal-ions away from the biological conditions necessary to produce ROS, thus quenching the redox cycling in vivo


**Lincoln, K. M.; **Gonzalez, P.; Richardson, T. E.; *Rutter, L.; Julovich, D. A.; Simpkins, J. W.; Green, K. N. “A potent antioxidant small molecule aimed at targeting metal-based oxidative stress in neurodegenerative disorders.” Chem. Commun. 2013, 49, 2712-2714. DOI:10.1039/C2CC36808K


A dynamic interplay of reactive oxygen species, metal-ions and amyloid are involved in the development of Alzheimer’s disease. L1 (pyclen) is capable of both preventing and disrupting Cu2+ induced AB1−40 aggregation. The L1 pyridine backbone engenders antioxidant capacity, as shown by cellular DCFH-DA (dichlorodihydrofluorescein diacetate) assay in comparison to other N-heterocyclic amines lacking this aromatic feature. L1 also prevents cell death induced by oxidative stress as shown by the Calcein AM assay. The results are supported using density functional theory studies which show that the pyridine backbone is responsible for the antioxidant capacity observed.

**Lincoln, K. M.; **Gonzalez, P.;Richardson, T. E.; *Rutter, L.; Julovich, D. A.; Simpkins, J. W.; Green, K. N. “An N-heterocyclic amine chelate capable of anti-oxidant and amyloid disaggregation” ACS Chem. Neurosci. 2012, 3, 919-927. DOI: 10.1021/cn300060v

5 6

Macrocycle L1 and L2 are capable of both disrupting and preventing the Cu(II)-induced formation of beta-amyloid plaques in vitro by binding copper-ions. In addition, the N-heterocyclic backbones possess antioxidantand radical scavenging properties, and demonstrate the ability to protect cells (Fibroblasts from a Friedreich's Ataxia patient) against death induced by reactive oxygen species. Notably, the hydroxyl substituted ligands (L2 and L3) display superior antioxidant and radical reducing capability compared to the pyridine-based macrocycle (L1). 


**Paulina Gonzalez, **Viviana C.P. da Costa, *Kimberly Hyde, Qiong Wu, Onofrio Annunziata, Josep Rizo, Giridhar Akkaraju, Kayla N. Green, ‘Bimodal-hybrid heterocyclic amine targeting oxidative pathways and copper mis-regulation in Alzheimer’s disease’ Metallomics, (2014), DOI:   10.1039/c4mt00161c.


A hybrid molecule composed of lipoic acid and the metal binding cyclen core are shown to protect cells from damaging copper ions and amyloid proteins via multi-modal pathways that involve antioxidant capacity and control of metal-ions.



*TCU Undergraduate Student, **TCU Graduate Student


-- Chemistry Department -- Texas Christian University --