To Examin the Relationship between Structure
and Activity for Inosine monophosphate dehydrogenase
(IMPDH) Inhibitors
Inosine monophosphate dehydrogenase
(IMPDH) inhibitors are the focal point of interest
for Dr. Bruce S. Burnham and his research group at
Rider University. IMPDH inhibitors with synthetic
nucleoside derivatives have been shown to be valuable
in treating viruses and tumors. Pyrrole nucleosides
have not yet been shown to inhibit IMPDH in the literature,
and so it would be useful to develop synthetic methods
for such compounds which would lead to a new group
of anticancer and/or antiviral drugs. Five member
ring C- and N-nucleoside analogues as well as 2,3,4-trisubstituted
pyrrole derivatives of marine natural products have
been shown to have antivral and anticancer activities,
respectively, through IMPDH inhibition, therefore
it is anticipated that pyrrole derivatives containing
a ribose substituent would be useful against cancer
or viruses.
The objective of this research project
is to develop methods in which pyrrole nucleosides
with a ribose group at the nitrogen, four or five
position on the pyrrole derivatives of marine natural
products can be synthesized. Successful synthesis
of such derivatives will allow the examination of
the relationship between structure and activity for
IMPDH inhibition. Kinetic studies of IMPDH with the
pyrrole nucleoside inhibitors will also be performed
by a collaborating group to determine if the synthesized
compounds are in fact IMPDH inhibitors and would indicate
whether the pyrroles compete with IMP or NAD+ to cause
their enzyme inhibition.
My contribution to this research project
over the ten-week period will be synthesizing different
pyrrole N-nucleosides via an SN2 reaction using NaH
in CH3CN or DMF and a protected ribose with a leaving
group (e.g., -Cl, -Br, 4-nitrobenzoate) on the anomeric
carbon. Subsequently, the new pyrrole nucleosides
will be tested for cytotoxicity in vitro in the following
leukemia cells lines: murine L-1210 lymphoid leukemia,
human Tmolt-3 acute lymphoblastic T-cell leukemia,
human Tmolt-4, HL-60 and THP-1.
The method that will be used to form
the N-glycosidic bond connecting the pyrrole nitrogen
to the ribose will be a reaction of the ribosyl chloride
or related derivative with the sodium salt of the
pyrrole, formed by treating the pyrrole with NaH in
CH3CN. Sodium methoxide in methanol will then be used
to deprotect the benzoyl groups at the 2í,3í
and 5í postions on the ribose. A transglycosylation
reaction will be an alternative method for the synthesis
of the N-glycoside and is especially useful in adding
a modified ribose to the pyrrole. In this alternative
method, a TMS-pyrrole will be formed in situ using
TMS-Cl and HMDS after which a protected pyrimidine
nucleoside will be added.
Activities
Associated with Award
Meeting/Poster Presentation:
Presented at the ACS
meeting at Rider University, NJ. August 2006.
Presented at Bryn
Mawr College Summer Science Internship and Fellowship
Poster Session Sept. 7th, 2006.
