Synthesis of AlphaSulfone Oligonucleotides

1
Synthesis of Alpha-Sulfone Oligonucleotides Crysta
l Henkel-Kimmes, Mentor Zhan K. Xue, Krishnan P.
Nambiar, Ph. D., Department of Chemistry,
University of California, Davis
















ABSTRACT The objective of this is experiment is
the synthesis of alpha oligodeoxynucleotides with
sulfone linkages. These oligomers are capable of
binding to the duplex DNA and forming a triple
helix, thus blocking transcription. In this way,
we can prevent specific genes (eg. oncogenes)
from being expressed. At the translation stage,
translation initiation sites on messenger RNA can
be blocked by the alpha-sulfone oligonucleotide,
thus preventing transfer RNA from binding to
ribosomes, thereby inhibiting protein synthesis.
Our synthesis begins with 2-Deoxy-D-Ribose. We
will introduce nucleobases onto the anomeric
carbon in the alpha orientation. Then, through a
series of synthetic reactions, we will introduce
one additional carbon atom at C-3 and C-5 each.
These modified alpha nucleosides will be used as
the building blocks in the oligomer synthesis.








BACKGROUND Gene expression is the process we are
controlling in this experiment. A DNA strand is
a double helix of nucleotides. Different
sequences of these nucleotides are transcribed
and translated into proteins. These proteins
control many different aspects of basic living.
When a gene is made into a protein, a number of
steps are involved.








First, the DNA molecule opens, and one of the
strands is transcribed. Next, this copied strand
goes to the ribosome, where it is translated into
a protein. The oligonucleotide we are
synthesizing has two possibilities for
interaction.
Beta








One, the molecule is specific to a set of
nucleotides. This molecule will then bind to one
side of that gene in the original DNA molecule
before it has the chance to be transcribed. This
prevents that certain gene from being expressed
because it stops the process at step one.
Alpha








The other place intervention can take place is at
the ribosome. The molecule we synthesized will
bind to the binding site of the ribosome,
preventing the transcribed RNA molecule from
being translated into a combination of amino
acids.








CHEMISTRY We made two modifications to the
natural DNA oligonucleotide. One such
modification to a DNA strand is having an alpha
oriented base. The increased stability of this
molecule is shown in a melting curve in
comparison to a helix with beta oriented bases.
The other modification we have made to the basic
double helix model is connecting the nucleotides
with sulfone groups instead of phosphate groups.
For one thing, the absence of negative charges on
the sulfone model allow it to penetrate the
plasma membrane easier. Also, when the molecule
is inserted into a cell molecules with phosphate
linkages tend to break down more than molecules
with sulfone linkages. This break down is due to
the enzymes we have in our bodies that recognize
phosphourdiester bonds.








Alpha-Sulfone Linkage
Phosphourdiester Linkage
Synthetic Scheme

Acknowledgements
I would like to thank Dr. Nambiar, Zhan Xue,
Ellen Robert and the UCLEADS program.