J. Westerberg

Jacob WesterbergOrganometallic ChemistryProf. MiesslerPaper 2

Application of Organometallic Compounds to Alzheimer’s Disease

Currently, Alzheimer’s disease (AD) has no cure or treatment options. It is also fatal in

all cases with persons diagnosed usually passing within a few years. Although there currently are

no options in combating the disease, we do know the pathological abnormalities that lead to the

rapid neurodegeneration. Two indicators, amyloid plaques (composed of amyloid -peptides

[A]) and neurofibrillary tangles (composed of hyperphosphorylated tau proteins) are present in

all cases of AD and have become targets of research.1 In considering organometallic compounds,

A are of greater interest. This is because the A has a metal-binding motif found near the N-

terminus where an organometallic compound can bind to. By binding to the this location, the

compound stops A aggregation.2,3 In 2008, Barnham and colleagues determined that this

hypothesis indeed attenuated A aggregation in vitro.4 Yellol and colleagues in 2015 have

continued research into this treatment possibility by exploring variations of an organometallic

compound that can hurdle other biological obstacles that are faced when introducing a drug into

the central nervous system.5 By experimenting with Iridium (III), Ruthenium (II), and Platinum

(II) complex variations, Yellol and colleagues have designed an assortment of compounds with

varying chemical properties that have potential to cross the blood-brain barrier and could be

nontoxic to cortical neural tissue. In one complex, it is even observed that there is rescue from

A toxicity. This recent work has shown promising results in treating neurodegenerative

diseases. Through understanding it, it becomes possible to organize possibilities for in vivo and

later clinical applications.

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In continuing the research of

Barnham and colleagues, Yellol and

colleagues wanted to be more conscious

of the factors that pose a hindrance prior

to and after the desired binding at A.

Sophisticated design of molecular

structure became crucial in overcoming

these challenges. The first consideration

was the necessary chemical properties

that would allow for the compound to

cross the blood-brain barrier. In total,

three compounds were synthesized with

three different transition metals: Ir, Ru,

and Pt. Each metal was bound to a metal

coordination ligand whose structure

remained consistent between complex

variations. A slow leaving ligand and a fast leaving ligand were the primary differences between

complexes and whose structures altered the lipophilicity and hydrophilicity of the compound.

These properties varied in such a way as to have

multiple options for crossing the barrier.

Chlorine was used across all compounds as the

fast leaving ligand while the slow leaving ligand

was either an arene or chlorine. Figure 1 depicts

the four major groups of the organometallic

complexes. The synthesis of the three complexes

can be seen in Figure 2. The primary precursor

for all compounds was pyridyl-benzimidazole (2

in Figure 2). The Pt complex (3 in Figure 2) was synthesized from the precursor with

Pt(DMSO)2Cl2 at room temperature for 24 hours. The Ru complex (4 in Figure 2) was formed

Figure 1. Individual pieces of organometallic compound

Figure 2. Scheme for the synthesis of the three organometallic complexes

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from the precursor with [6-p-cymene)RuCl2]2

in methanol. Lastly, the Ir complex (5 in Figure

2) was created in a similar manner; the

precursor with [5-C5Me5)IrCl2]2 in methanol.

After synthesis, all complexes were confirmed

using mass spectrometry and NMR

spectroscopy. Figure 3 shows the x-ray

crystallography of the Ir complex. It should

also be known that the complexes after synthesis organize into diamagnetic compounds because

of weak interactions occurring between the ring components of the metal coordination ligands

(Figure 4). Although the ability to cross the blood brain barrier was not directly addressed in

their experiments, they went about it in such a way that there are now multiple complexes to test

in vivo later.

After synthesis, the compounds needed to be

tested to determine whether or not they had the

properties necessary to inhibit A aggregation

like the compounds Barnham and colleagues used. To do this, Yellol and colleagues tested each

of the complexes using a thioflavin T fluorescence assay. Through introduction of each complex

to an A42 sample, they found that 1M concentration of each compound was enough to inhibit

aggregation of A. This was then confirmed using transmission electron microscopy. By

demonstrating that their complexes have this capability and have potential to cross the blood-

brain barrier, they are one step closer to a biologically useful complex. Two additional facets

they explored were whether any of their complexes were toxic to cortical neural tissue and

whether or not they could rescue the tissue from the toxic A after inhibition of aggregation. In

vitro samples of mouse cortical neural tissue were prepared in media and evaluated after four

days in four ways: no additions to media (control), addition of one organometallic complex only

(1.25M), addition of A42 only (10M), and addition of one organometallic complex (1.25M)

and A42(10M). Results (Figure 5) are insignificant for the Pt complex and show the Ru

complex as inherently toxic, even more so than the A42. The Ir complex demonstrates rescue

from toxicity. While all complexes inhibit

aggregation of A, this experiment gives more

Figure 4. Model of diamagnetic compound interactions

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valuable information. It is clear that the Ru complex is less than ideal as it damages the neural

tissue and would do more harm than good in treating AD. The Pt complex has potential as it

stops aggregation and isn’t toxic. The best candidate, though, is the Ir complex where not only

does it have both those qualities, but it also rescues the neural tissue from the A toxicity.

It was the goal of this research by Yellol and

colleagues to synthesize more biologically relevant

organometallic compounds to treat AD. Prior

research has determined that inhibiting aggregation

of A is possible by a metal binding at the N-

terminus. Before binding, the complex must make it

to the cortical neural tissue of the brain where A is

found. Therefore, it must cross the blood-brain

barrier, a notoriously difficult obstruction to diffuse

across as it protects the central nervous system from

toxins. Yellol and colleagues designed three

different complexes with variable ligands that adjust

the compounds lipophilicity and hydrophilicity in

hopes that one will be able to cross the blood-brain

barrier in vivo. The three complexes were also tested

and found to stop A aggregation. One was found to

be toxic to neural tissue and another rescued neural

tissue from damage done by A. Taking into

consideration these results, they found two

compounds with potential in vivo relevance. This

takes the field one step closer to identifying a

treatment option for AD sufferers through

organometallics.Figure 5. Results of neural tissue rescue experiment a. Pt complex b. Ru complex c. Ir complex

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References

(1) Kenche, V. B.; Hung, L. W.; Perez, K.; Volitakes, I.; Ciccotosto, G.; Kwok, J.; Critch,

N.; Sherratt, N.; Cortes, M.; Lal, V.; Masters, C. L.; Murakami, K.; Cappai, R.; Adlard,

P. A.; Barnham, K. J. Angew. Chem. 2013, 52, 3374.

(2) Valensin, D.; Gabbianib, C.; Messori, L. Coord. Chem. Rev. 2012, 256, 2357.

(3) Hureau, C.; Faller, P. Dalton Trans. 2014, 43, 4233.

(4) Barnham, K. J.; Kenche, V. B.; Ciccotosto, G. D.; Smith, D. P.; Tew, D. J.; Liu, X.;

Perez, K.; Cranston, G. A.; Johanssen, T. J.; Volitakis, I.; Bush, A. I.; Masters, C. L.;

White, A. R.; Smith, J. P.; Cherny, R. A.; Cappai, R. Proc. Natl. Acad. Sci. U.S.A. 2008,

105, 6813.

(5) Yellol, G. S.; Yellol, J. G.; Kenche, V. B.; Liu, X. M., Barnham, K. J.; Donaire, A.;

Janiak, C.; Ruiz, J. Inorg. Chem. 2015, 54, 470.

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