Date of Award
Spring 2019
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Chemistry
First Advisor
Dockendorff, Chris
Second Advisor
Donaldson, William A.
Third Advisor
Timerghazin, Qadir
Abstract
Invasive fungal infection is a life-threatening illness that causes high mortality, and is especially common among patients with compromised immune systems. However, currently there are only three major classes of clinically useful drugs capable of treating such infections. In addition, due to the fact that drug resistance has become a serious issue especially among patients who suffer from chronic infections, it is urgent to identify new drug candidates, particular those of new classes. The discovery of the natural product sordarin and its novel mechanism of action of inhibiting fungal protein synthesis via the fungal eukaryotic elongation factor 2 (eEF2) led to the development of a new class of antifungal agents that target eEF2. Despite the extensive efforts of multiple pharmaceutical companies striving to identify a clinically useful agent from this class, there has been no analog that has successfully reached clinical trials, perhaps due to unsatisfactory pharmacokinetic profiles or limited spectra of activity. This study mainly focused on the synthesis of a series of simplified bicyclic sordarin analogs. By switching the parent sordarin molecule’s metabolically unstable cyclopentane to a more metabolically stable substituent, an improved pharmacokinetic profile could be achieved. This function-oriented synthesis approach also allows a more facile synthesis as compared with reported total syntheses. Two generations of novel bicyclic sordarin analogs were synthesized featuring a Diels-Alder reaction using a functionalized silyloxy-cyclopentadiene. The 1st-generation synthesis furnished an analog maintaining the minimum pharmacophore of a bicyclic carboxylic acid vicinal to a nitrile or aldehyde. In subsequent studies, five different strategies for constructing a C-2 quaternary center on the bicyclo[2.2.1]heptane core were studied in detail, and a synthetic route featuring a stereoselective alkylation at C-2 was developed, which gives access to more sophisticated bicyclic sordarin analogs, including those with glycone moieties. Five bicyclic sordarin analogs were synthesized and assessed against C. albicans, C. parapsilosis, P. variotii and A. fumigatus. Although no antifungal activities were observed up to 8 µg/mL, the established synthetic route will enable unique structure-activity relationship (SAR) studies that could generate promising antifungal agents targeting eEF2.