A novel pyrrole synthesis and the synthesis and biological evaluation of a new topoisomerase I inhibitor

Pamela Mari Nagafuji, Purdue University

Abstract

The development of new methodologies for the synthesis of substituted pyrroles has been encouraged by the exploitation of the pyrrole ring system as an intermediate in the synthesis of natural products. A traditional and widely used method for preparing substituted pyrroles from amino acids relies on the condensation of α-amino ketones with carbonyl compounds that contain a reactive α-carbon. This preparative procedure, developed by Knorr, was first reported in 1884. The synthesis described in this work will demonstrate a novel approach which also employs amino acids as precursors. The versatility of this method affords a short route to highly substituted pyrroles and is suitable for the preparation of fused pyrrole ring systems. The identification of a new inhibitor of topoisomerase I will be described. The cytotoxic alkaloid was initially discovered as a topoisomerase I inhibitor through screening efforts initiated at the National Cancer Institute. The structure-activity relationships surrounding this compound had not been previously explored and initial efforts were made to synthesize appropriate analogs of the indeno[1,2-c]isoquinoline of interest and examine the contribution of topoisomerase I inhibition towards the demonstrated cytotoxicity.

Degree

Ph.D.

Advisors

Cushman, Purdue University.

Subject Area

Organic chemistry|Biochemistry

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