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Synthesis
of Inhibitors for Matrix Metalloproteinases
As
part of a multimillion dollar collaborative program with the Center
for Protease Research, we are undertaking the synthesis
of inhibitors for matrix metalloproteinases. These enzymes
are responsible for normal tissue remapping in the body. For
example, they help maintain joint tissues, regulate the blood-brain
barrier, and are involved in every part of the body. Many diseases
such as cancer, multiple sclerosis, arthritis, etc, show unusual
levels of MMPs and it is thought that inhibition of these enzymes
may lead to important treatments for these diseases. MMPs are
characterized
by a catalytic zinc atom in the active site. Key to inhibition
of these enzymes with small molecules is the presence of a
group which can bind this zinc atom. Also, a hydrophobic group
which can bind in the S1' hole of the MMPs increases the inhibitory
activity and selectivity of organic inhibitors. In our program
we are preparing new MMP inhibitors based on heterocyclic zinc
binding groups as well as phosphinate transition state analogs.   
MMP2 Catalytic Domain
We
have developed a set of small molecule inhibitors based
on our oxazoline template as a unique and novel zinc-binding
group. We have discovered several lead compounds that we
are currently optimizing.
Synthesis
of Inhibitors for Histone Deacetylases
Histone
Deacetylase is an enzyme involved in the regulation of gene
transcription. It removes the acetate groups off of the lysine
residues of histones, thus turning off gene expression. In
diseases such as cancer, lupus and Huntington's disease,
the regulation of histone acetylation is out of balance.
HDAC inhibitors have been shown to be effective in cancer
chemotherapy. We are developing novel HDAC inhibitors for
this interesting zinc-enzyme.
Molecular graphics images were produced using
the UCSF Chimera package from the Computer Graphics Laboratory,
University of California, San Francisco (supported by NIH
P41 RR-01081). |
© 2000-2007
