Download CHEM252: Organometallics and Alzheimer`s

J. Westerberg 1
Jacob Westerberg
Organometallic Chemistry
Prof. Miessler
Paper 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 Nterminus 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.
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
Figure 1. Individual pieces of
organometallic compound
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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
Figure 2. Scheme for the synthesis of the three
organometallic complexes
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 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
Figure 3. X-ray crystallography of the
Ir complex
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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.
Figure 4. Model of diamagnetic compound
 interactions
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 A42 sample, they found that 1M 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 bloodbrain 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
(1.25M), addition of A42 only (10M), and addition of one organometallic complex (1.25M)
and A42(10M). Results (Figure 5) are insignificant for the Pt complex and show the Ru
complex as inherently toxic, even more so than the A42. The Ir complex demonstrates rescue
from toxicity. While all complexes inhibit aggregation of A, this experiment gives more
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.
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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 Nterminus. 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
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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,
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(5) Yellol, G. S.; Yellol, J. G.; Kenche, V. B.; Liu, X. M., Barnham, K. J.; Donaire, A.;
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