Studies on the Synthesis, Function, and Properties of Troponoids
Troponoids are a unique class of non-benzenoid aromatic compounds with a wide range of demonstrated applications in pharmaceuticals and molecular sensing. The cycloheptatrienone scaffold possesses a noteworthy degree of tunability as a function of ring oxygenation. This manuscript describes our efforts toward a better understanding of the physical consequences of the scaffold to better utilize the motif. Chapter the first discusses our efforts at elucidating the mechanism of troponoid inhibition of the Hepatitis B virus reverse transcriptase RNAse H enzymatic domain. Using homology modeling in conjunction with traditional in vitro assays we were able to establish the likely mechanism of action for troponoid based inhibitors while simultaneously elucidating engageable elements of the enzyme active site. This study allowed us to refine our inhibitor design; leading to the discovery of a new class of fluorescent small molecule sensors. We also identified crucial deficiencies in our understanding of tropolone structural properties, necessary to the efficient development of troponoid based therapeutics. Chapter 2 describes our efforts in understanding troponoid atropisomerism – probing the limits of the stabilizing influence of the scaffold on the rotation of appended groups. Here we discuss our use of a dimerized oxidopyrylium ylide in [5+2] cycloadditions to generate novel tropolone probes for studying the rotational barriers of ketones appended to tropolones. These novel structures were subjected to variable temperature nuclear magnetic resonance spectroscopy, and various racemization studies to quantify the enhancement in rotational energy barriers of a small library of tropolone-ketones. Computational methods were employed to predict energy barriers of the structurally analogous benzenoids and corroborate experimental barriers. Overall, demonstrating the general tendency of the tropolone scaffold to enhance configurational stability among its substituents with few exceptions. The third chapter discusses our discovery and analysis of the magnesium activated aqueous fluorescence of tropolone derivatives. Through a newly developed, late-stage lactam formation protocol, we access a library of lactam appended tropolones with promising properties for the development of novel magnesium selective fluorescent sensors. We also perform an aqueous fluorescence structure activity relationship study of several previously characterized tropolone structures inspired by the discovery of the magnesium activated fluorescence of α-hydroxytropolone. We demonstrate the tendency of troponoids to interact electronically with magnesium and calcium and potentially serve as a binding site for the development of novel sensors. We conclude with aqueous fluorescence titrations of our lactam appended tropolone, demonstrating its highly favorable characteristics for development as a magnesium selective fluorescent dye.
Computational Chemistry, Organic Chemistry, Physical Chemistry, Rotational Barriers, Fluorescence, Docking, magnesium sensor, hydroxytropolone
City University of New York - Graduate Center
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The Graduate School and University Center of The City University of New York