Design, synthesis, and biological evaluation of aromathecins, indenoisoquinolines, and related compounds as topoisomerase I inhibitors

Maris Angela Cinelli, Purdue University

Abstract

The following dissertation describes the design, preparation, and bioassay of several classes of topoisomerase I (Top1) inhibitory alkaloids. Although some Top1 inhibitors (derivatives of the natural product camptothecin, or CPT) are currently used as effective anticancer agents, their many drawbacks make the discovery of alternatives highly desirable. The diazadibenzofluorenone system, based on the natural product 22-hydroxyacuminatine, can be considered a "composite" or "hybrid" of two other classes of Top1 inhibitors - the camptothecins and the indenoisoquinolines. These compounds lack the metabolically labile hydroxylactone moiety of the former class; it has been replaced by a benzene ring. Substituted diazadibenzoflurenones are called "aromathecins." An efficient total synthesis of the aromathecin system has been accomplished using a pyrroloquinolinedione Friedlander condensation strategy. Numerous aromathecins, substituted at position 14, the A-ring, E-ring, or some combination thereof, have been prepared and assayed against Top1 and human cancer cell lines. Many of these compounds possess promising anti-Top1 and antiproliferative activity. Interestingly, the aromathecin structure-activity relationship (SAR) itself is a "hybrid" of the indenoisoquinoline and camptothecin SARs, and molecular modeling and docking studies provide insight into the mechanism of action of these compounds. The second study described herein describes the attempted preparation of analogues of the natural product luotonin A. This pyrroloquinazolinoquinoline alkaloid, isolated from Peganum nigellastrum, also has Top1 inhibitory and antiproliferative activity. As it is very similar in structure to the aromathecin core, it was envisioned that it could be synthesized and derivatized in a similar fashion. Although the analogues could not be prepared, various synthetic efforts are given. The third study describes the preparation of putative metabolites of the clinical indenoisoquinoline candidates LMP 776 (indimitecan) and LMP 400 (indotecan). Several potential metabolites were identified from murine metabolism studies. These analogues (arising from cleavage of the methylenedioxy group of the indenone ring) were prepared by condensation of dimethoxyhomophthalic anhydride with the appropriate Schiff base, and oxidative cyclization of the resulting cis-acid. Highly potent Top1 inhibitory activity was observed for some of these compounds, and a complete characterization of their bioactivity profiles is underway.

Degree

Ph.D.

Advisors

Cushman, Purdue University.

Subject Area

Organic chemistry|Pharmacy sciences

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