2006 Off Campus Research Internship Awardee

Bhumika Patel (Chemistry)


Activities Associated with Award

Mentor: Dr. Bruce S. Burnham (Rider University)


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.

  • Poster Title: "The Synethesis of Pyrrole Nucleosides as Anticancer and Antiviral Agents." Bhumika Patel, Bhavik Patel, Bruce S. Burnham. Rider University, Dept. of Chemistry, Biochemistry and Physics.

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