1. Synthesis and DNA Binding of
[Ru(bpy)2(dcbpy)]PF6
Tim W. Chapp '05 and Dr. S. Glazier, Advisor
2. Synthesis of Cyanoguanidines
as Potential Vanilloid Receptor Ligands
Joseph Jablonski '05 and Dr. L. French, Advisor
3. Metallacrowns, Ruthenium Complexes
and DNA Binding: New Molecules and a Binding Redux
Paul A. Kloek '05 and Dr. Neil A.
Law, Advisor
4. DNA Binding Studies of Two New
Classes of Metal Complexes
Ariel Riezenman, Heuer Fellow; and Dr. S. Glazier, Advisor
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Synthesis and DNA Binding of
[Ru(bpy)2(dcbpy)]PF6
Tim W. Chapp '05 and Dr. S. Glazier, Advisor
DNA is a complex biological molecule
that influences everything from ones hair color to the likelihood of getting
cancer. As such, compounds that have the ability to identify specific regions
of DNA, or alter the functionality of DNA in a specific way are useful to study.
Molecules that intercalate have the ability to weave in portions of their structure
between the base pairs of DNA.(1) Once a molecule is bound to DNA in this way;
both the structure and function of DNA are altered. From a medicinal standpoint,
understanding site specific intercalation will increase the understanding of
how to develop pharmaceuticals that require binding to DNA to inhibit harmful
replication, for example, the growth of cancerous cells.(2)
Ruthenium polypyridyl complexes are water soluble, luminescent, and stable making
them easy to work with and attractive candidates as possible intercalators.
The goal of our research is to synthesize, characterize and study the intercalation
properties of Ru(bpy)2(dcbpy). By adding the 3,3'-dicarboxy-2,2'bipyridine (dcbpy)
ligand we hope to make comparisons between the characteristic properties of
Ru(bpy)3 and Ru(bpy)2(dcbpy). We have found that Ru(bpy)2(dcbpy), when compared
to Ru(bpy)3, shows a reduction in quantum yield (F), extinction coefficient
(e), and its Stern Volmer (Ksv) constant when quenched by potassium ferricyanide.
However, unlike Ru(bpy)3, Ru(bpy)2(dcbpy) shows good binding affinity to DNA.
Further work is required to determine the binding mechanism of Ru(bpy)2(dcbpy).
(1) Erkkila, K. E.; Odom, D. T.; Barton, J. K. Chem. Rev. 1999. 99, 2777-2795.
(2) Wilhelmsson, L. M.; Westerlund, F.; Lincoln, P.; Norden, B. J. Am. Chem Soc. 2002, 124, 12092-12093.
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Synthesis of Cyanoguanidines
as Potential Vanilloid Receptor Ligands
Joseph Jablonski '05 and Dr. L. French, Advisor
Abstract:
Discovering and isolating natural products opens a window of opportunity to study important biological processes. It has been observed that capsaicin has novel analgesic activity involving the vanilloid receptor 1 (VR1; TRPV1) a ligand-gated ion channel. Capsaicin is a natural product that has been isolated from Capsicum annuum, the red peppers. Via agonism at VR1 receptors, capsaicin excites and then desensitizes a subset of primary neurons involved in nociception, neurogenic inflammation, and a variety of local regulatory functions. This receptor is also activated by protons, heat, resiniferatoxin (RTX) and arachidonic acid derived signaling molecules. Both desensitizing agonists and antagonists have potential use as pain killers. Novartis created a series of compounds, based on urea and thiourea pharmacophores, which have been shown to have activity at VR1. Using a combinatorial approach, a small library of 25 different cyanoguanidine analogs will be synthesized. These compounds will be based on the Novartis compounds. In this approach, bioisosteric replacement of urea and thiourea moieties with an N-cyanoguanidine functional group will be carried out. In doing this, it is hoped that new compounds can be discovered which might display higher binding affinities as agonists or antagonists at TRPV1. The methodology is amenable to rapid synthesis of large numbers of ligand candidates.
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Metallacrowns, Ruthenium Complexes
and DNA Binding: New Molecules and a Binding Redux
Paul A. Kloek '05 and Dr. Neil A.
Law, Advisor
Metallacrowns are a unique class of inorganic clusters that form interesting structural motifs with a high concentration of metal ions at their cores.1 Many metallacrowns form planar molecules with an aromatic periphery that bear a structural resemblance to a porphyrin. Porphyrins are known to bind to DNA with the potential to modify DNA function, for example to stop cell growth in tumors.2 DNA binding by metallacrowns, however, has not been reported in the literature. Therefore, known metallacrowns with salicylhydroxamic acid and 3-hydroxyl-2- naphthohydroxamic were prepared in order to analyze their ability to bind DNA. The DNA binding studies were then conducted in collaboration with Dr. Glazier's research group. The effect of the aromatic ring structure and the overall charge of the complex were two of the factors potentially addressed by these complexes. Early results indicated that the cationic complexes may bind to DNA, whereas the anionic complex showed little binding affinity. Further analysis is warranted. Previously in this lab, three different isomers of [Ru(dcbpy)(bpy)2]PF6 were synthesized and the binding interactions with calf thymus DNA of each were investigated.3 Despite only slight structural differences between each isomer, viscosity and spectroscopic titrations showed evidence of binding by intercalation when the carboxyl groups are substituted at the 3,3' positions of dcbpy. One possible explanation of the observed isomeric differences is the presence of Sephadex® in the filtration of the 3,3' isomer. Several synthetic modifications were employed to determine the possible role of Sephadex in DNA binding studies carried out in this lab and in other research groups.
1) Pecoraro, V. L., et al., Prog.
Inorg. Chem., 1997, 45, 83-177.
2) Pasternack, R. F., et al.,. Biophys. J. 1998, 75, 1024-1031.
3) Chapp, T. W. and Glazier, S., unpublished results.
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DNA Binding Studies of Two New
Classes of Metal Complexes
Ariel Riezenman, Heuer Fellow; and Dr. S. Glazier, Advisor
Past research has shown that some
molecules bind to DNA usually by one or more mechanisms such as electrostatic
interactions, groove binding or intercalation.1, 2 Compounds that have the ability
to bind specific regions of DNA alter the functionality of DNA in a specific
way. Medical applications include pharmaceuticals that inhibit replication,
for example, the growth of cancerous cells. The series of complexes shown in
figure 1 are of interest because they include transition metal polypyridyl complexes
which are water soluble, luminescent, and stable. The ligand is a terpyridinyl
derivative capable of forming complexes with ruthenium, cobalt and iron which
are referred to as chiral monsters. Employing two different linkers, one rigid
and the other flexible, dimers and polymers complexes can be isolated. Dimer
complexes have the potential to become irreversibly threaded between DNA base
pairs. The binding mechanisms of dimers are not well understood. Viscosity,
fluorescence spectroscopy and Uv-Visible absorbance spectroscopy were used to
characterize the binding mechanisms and relative binding strengths of compounds
from the chiral monster series. From this work we hope to better understand
the effects of linker rigidity, type of metal ion and chain length.
The DNA binding potential of the relatively planar and charged copper and manganese
based metallacrowns currently being synthesized by Neil Law's group is intriguing,
particularly because of the absence of research in this area. Preliminary DNA
binding studies suggest a complicated interaction and the need for new experimental
methods. Research by Robert F. Pasternack3 and others show that porphyrins,
which are structurally similar to metallcrowns, form complexes with DNA and
we expect to discover associated behavior for metallcrowns.
Figure 1: Schematic representation of the 2,2':6',2''-terpyridine complexes
of ruthenium CM, CD and RCD and the corresponding ligands [ctpy-X-ctpy] and
[ctpy-B-ctpy].
(1) Foye, W. O., Ed.; In Cancer
Chemotherapeutic Agents; 1995; , pp 698.
(2) Metcalfe, C.; Thomas, J. A. Chem. Soc. Rev. 2003, 32, 215-224.
(3) Pasternack, R. F.; Goldsmith, J. I.; Szep, S.; Gibbs, E. J. Biophys. J.
1998, 75, 1024-1031.(return to top)
SUMMER STUDENT RESEARCH funded by the Russell Pearce and Elizabeth Crimian
Heuer Foundation, 2005
We gratefully acknowledge financial
support from the Heuer Fellowship
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