DOI
https://doi.org/10.25772/60C9-3491
Author ORCID Identifier
Defense Date
2017
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Chemistry
First Advisor
Vladimir Sidorov
Second Advisor
Ashton Cropp
Third Advisor
Matthew Hartman
Fourth Advisor
Indika Arachchige
Fifth Advisor
Hamid Akbarali
Abstract
Small molecule synthesis has become a valuable tool in the study of biological systems. Biologically active compounds can be designed based on well-characterized endogenous systems or they can be found through the screening of large libraries of small molecules. This work involves the development of a small library of cyclic thiourea-based small molecules by use of an unreported synthetic pathway. Briefly, parent thioureas were cyclized by reaction with bromoacetyl bromide, and one or two isomeric heterocycles were found to form. Further studies indicated that the reaction could be easily manipulated by temperature or solvent to effectively control the product distribution. These iminothiozolidinones were characterized by single crystal x-ray analysis. The new reaction was explored in an effort to uncover the factors influencing the control of the isomer formation. Furthermore, these iminothiozolidinones underwent a novel decyclization reaction that resulted in the loss of the parent thiourea connectivity and incorporation of an external nucleophile to yield an aminooxoethylcarbamothionate. The reaction proceeds through a termolecular mechanism. These reactions can be combined to a one-pot reaction series. These compounds share similarities with a class of compounds reported to be known HIV-1 reverse transcriptase inhibitors94. In addition to these new synthetic reactions, work was conducted with a previously developed cyclen thiourea receptor for the anionic dye HPTS and its derivatives50-52. This system was used to develop a cell labeling assay that led to the amplification of fluorescent labeling of target cells through the use of liposomes. Briefly, a dye-ligand conjugate for the glycine receptor was synthesized. Liposomes functionalized with the cyclen receptor were prepared encapsulating Rhodamine B. Confocal microscopy studies demonstrated the binding of the HPTS-ligand to the cell membranes. Addition of the liposomes resulted in quenching of the green fluorescence, indicating binding of the cyclen to HPTS. Subsequent excitation of Rhodamine B showed red fluorescence associated with the cells. The intensity of the red signal was demonstrably higher than for the signal resulting from the binding of the ligand-dye to the receptor. Together, these projects increase the synthetic usefulness of thiourea based small molecules and demonstrate the potential biological applications of related compounds.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
5-11-2017