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Inorganic Chemistry
Bioinorganic and Medicinal Chemistry
Dr. Nicola Brasch
http://dept.kent.edu/chemistry/Faculty/Research/brasch.htm
Our two main research interests are
vitamin B12 and the B12-dependent enzyme
reactions and the bioinorganic chemistry of vanadium complexes. This
year our research efforts have become more medicinally focused, which
is reflected by the change in the name of our group. Of the ~15
vitamin B12-dependent enzyme reactions known, two of these
reactions, involving methionine synthase and methylmalonyl-CoA
mutase, occur in humans. In the former reaction, the vitamin B12
derivative methylcobalamin is an intermediate in the methylation of
homocysteine by methyl-tetrahydrofolate. A current "hot topic"
in the medical literature is the recently demonstrated relationship
between high serum levels of homocysteine and a greatly increased
risk of strokes or heart attacks. In addition, there is increasing
evidence that individuals with high serum levels of homocysteine are
more likely to develop neurological disorders. This year we have
begun to collaborate with Dr Andrew McCaddon and his research team in
Wales, who are interested in the relationship between aberrant B12
metabolism and Alzheimer's disease.
Last
year we decided to embark upon a completely new area of research for
us: vanadium chemistry. This is finally beginning to pay off, and we
now have some exciting results concerning the types of complexes
formed between vanadium(III) and carboxylates. This is discussed in
more detail below.
This
year has also been one of much change with respect to personnel. In
January, Dr Robert Doyle from Trinity College, University of
Dublin, took up a one-year postdoctoral position, and in March, Dr
Fiona Fry from Monash University took up a similar position. Dr Ling
Xia left us in March to take up a postdoctoral position in the
GlaxoSmithKline research team. Sam Brodie from Massey University,
New Zealand, joined us for ten weeks on a summer vacation scholarship
from November 2001-February 2002.
In
July, Dr Brasch travelled to Europe and gave invited lectures at the
University of Sheffield and the Inorganic Coordination Chemistry
Conference (ICCC) in Heidelberg, Germany. Recently, Dr Brasch
accepted a tenure-track appointment at the Department of Chemistry,
Kent State University, USA, commencing in January 2003.
Using
Vitamin B12 as a Drug Carrier
Targeted
drug delivery, as opposed to systemic delivery, can dramatically
increase drug efficacy while minimizing the side effects associated
with administering high doses of drugs in a non-strategic manner.
Targeted delivery requires loading drugs onto molecular vehicles.
This requires that the drug be directly conjugated to, for example,
targeting proteins, vitamins, cytokines or antibodies. Vitamin B12
and its derivatives have very efficient intestinal absorption and
cellular uptake mechanisms. Vitamin B12/peptide and
vitamin B12/protein bioconjugates have already been shown
to have applications in the uptake of both peptides and proteins
administered orally. Over the past year we have synthesised a number
of vitamin B12 bioconjugates for the enhanced
transportation of drugs. (with R.P. Doyle)
Further Investigations on the Reaction between Methylcobalamin
and Cyanide
We
have re-investigated the cause of the 1H NMR
spectroscopy chemical shift changes observed for the reaction between
methylcobalamin and cyanide and found that cyanide actually binds at
the lower (a) axial site of
methylcobalamin, rather than simply forming an association complex.
(with S.J. Brodie, A.G. Cregan, and R. van Eldik
[U. Erlangen Nuremberg, Germany])
Determination of Activation Parameters for the Reaction between
Coenzyme B12 and Cyanide
The
mechanism of the reaction between coenzyme B12 and cyanide
has been a topic of much discussion in the B12 literature
over several decades. Recently we proposed a mechanism in which a
water molecule plays an important role in assisting Co-C heterolytic
bond cleavage. Determining activation parameters for Co-C
heterolysis provides us with a novel way to further probe our
proposed mechanism for this process, and confirmed that a solvent
molecule is indeed involved in the transition state of Co-C bond
cleavage. (with A.G. Cregan, and M.S.A. Hamza, R. van Eldik
[U. Erlangen Nuremberg, Germany])
Studies on the Interactions of Vanadium(III) with Acetate
Ascidians
of the suborder Phlebobranchia are small marine animals that
sequester vanadium(V) from seawater and reduce it to vanadium(III).
How or why these creatures accumulate this metal ion is unknown. In
addition, the chemistry of vanadium(III) itself, especially in
aqueous systems, is poorly defined compared with that of vanadium in
the more stable oxidation states of +4 and +5. Our studies of
vanadium(III) complexes have commenced with the acetate ligand, since
it is used as a buffer in the isolation of compounds from ascidian
blood cells, in addition to being a simple model for amino acids.
X-ray diffraction studies of V(III)-acetato complexes isolated from
aqueous solution have to date shown that at least two cationic
complexes are formed. The first compound is a tetranuclear species
with a ratio of acetate:vanadium of 1:1, while the second salt
isolated shows an acetate:vanadium ratio of 2:1, with a trinuclear
core. A titration study by 1H NMR spectroscopy
clearly demonstrates the presence of a 2:1 species in solution, as
well as the existence of a second species with a lower
acetate:vanadium(III) ratio. (with A.J. Edwards, F.H. Fry)
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