Date of Completion

10-5-2016

Embargo Period

10-5-2016

Keywords

tropolone leukemia Gram-negative bacteria enolase

Major Advisor

Dennis Wright

Associate Advisor

Charles Giardina

Associate Advisor

Akiko Nishiyama

Associate Advisor

M. Kyle Hadden

Associate Advisor

Jose Manautou

Field of Study

Pharmaceutical Science

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

Troponoid (more commonly, tropone/tropolone) refers to a family of naturally occurring compounds with a unique seven-membered aromatic ring. As with many secondary metabolites, many of the tropolones display a wide range of biological activity. This activity includes: antibacterial/antifungal, insecticidal, phytotoxic, antimitotic, anti-inflammatory, enzyme inhibition, anticancer and reactive oxygenated species (ROS) scavenging. Most of this broad-range activity is attributed to the tropolone moiety while side chains attribute to selectivity. Therefore, tropolone may offer a unique scaffold to develop antiproliferatives since it can chelate metal ions, is relatively small and most likely promiscuous, likely resulting in several mechanisms of action to diminish the development of resistantance.

This work focuses on the synthesis of a more diverse library of α-tropolones and tropones with functional groups capable of chelation other than the native hydroxyl. The library was used to assess structure activity relationship on the antiproliferative effects against cancer cell lines. Previous results with α-tropolones in the Anderson/Wright labs suggested selectivity towards hematological malignancies. As a result, α-tropolones were assessed for antiproliferative effects against a panel of malignant hematological cell lines from T-cell, B-cell and myeloid lineage. From this panel, there appears to be selectivity towards cell lines of T-cell lineage. The most susceptible cell line, Molt-4, was explored further to understand the mechanism through which α-tropolones exhibit antiproliferative properties.

Patients with leukemia are at the highest risk of potentially deadly infections typically caused by Gram-negative bacteria, with E. coli, K. pneumoniae, and P. aeruginosa being the most common and most lethal. Since several natural tropolones have been found to be bacteriostatic and bactericidal against a broad range of bacteria and exhibit lead-like Gram-negative antibacterial activity, α-tropolones may be developed as antiproliferative agents effective against both hematological malignancies and bacterial infections. The library of α-tropolones was then screened for antiproliferative effects on Gram-negative bacteria. Key potent tropolones were used to explore potential targets using an unbiased target identification approach. These studies show that bacterial enolase is most likely the target through which tropolones exhibit antiproliferative properties against Gram-negative bacteria.

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