Applications of Small Heterocycles: Oxetanes as Additives and Cosolvents and Oxazolines as Linkers for Controlled Release from Silica Nanoparticles

In the first chapter of this dissertation, the design and synthesis of bifunctional additives and cosolvents containing an oxetane moiety are described. The use of dimeric oxetanes as additives for reactions involving organometallic agents—namely, organolithium, organozirconium, and organomagnesium reagents was studied. A dimeric bisoxetanyl ether showed promise for solvating organolithium aggregates, but dimeric oxetanyl ethers were not useful additives in hydrozirconation reactions. A bisoxetanyl sulfide is being investigated further as an additive for Grignard reactions. A bisoxetanyl sulfoxide (MMS350) was developed as a dimethylsulfoxide substitute that showed utility for enhancing the aqueous solubility of small organic molecules. In the second chapter, efforts toward the development of agents for protection and mitigation of ionizing radiation damage are outlined. It was discovered that administration of MMS350 prolonged survival in irradiated mice. Moreover, mice given MMS350 in their drinking water had lower incidences of pulmonary fibrosis. Additional analogs of MMS350 were synthesized for further investigation of the molecular and structural requirements for successful sulfoxide-containing radiation protectors. In the third chapter, the design and proof-of-concept study of using an oxazoline linker for functionalization and pH-dependent release of reactive oxygen species (ROS) scavengers from silica nanoparticles is discussed. pH-Dependent hydrolysis of model oxazolines was achieved by modulating the substitution on the oxazoline moiety. Moreover, functionalized silica nanoparticles were successfully endocytosed by macrophages. Our studies have laid the groundwork for the design of covalently modified nanoparticles for delivery of ROS

Synthesis of 2,6-disubstituted dihydropyrans via an efficient BiBr3-initiated three component, one-pot cascade

The rapid synthesis of cis-2,6-disubstituted dihydropyrans is achieved in a three-component, one-pot cascade reaction. BiBr3-mediated addition of ketene silyl acetals or silyl enol ethers to beta,gamma-unsaturated cis-4-trimethylsilyl-3-butenal provides a Mukaiyama aldol adduct containing a vinylsilane moiety tethered to a silyl ether. Addition of a second aldehyde initiates a domino sequence involving intermolecular addition followed by an intramolecular silyl-modified Sakurai (ISMS) reaction. Isolated yields of this one-pot reaction vary from 44 to 80% and all compounds were isolated as the cis-diastereomers (10 examples). (C) 2009 Elsevier Ltd. All rights reserved

In Vivo Imaging of Multidrug Resistance Using a Third Generation MDR1 Inhibitor

Cellular up-regulation of multidrug resistance protein 1 (MDR1) is a common cause for resistance to chemotherapy; development of third generation MDR1 inhibitorsseveral of which contain a common 6,7-dimethoxy-2-phenethyl-1,2,3,4-tetrahydroisoquinoline substructureis underway. Efficacy of these agents has been difficult to ascertain, partly due to a lack of pharmacokinetic reporters for quantifying inhibitor localization and transport dynamics. Some of the recent third generation inhibitors have a pendant heterocycle, for example, a chromone moiety, which we hypothesized could be converted to a fluorophore. Following synthesis and teasing of a small set of analogues, we identified one lead compound that can be used as a cellular imaging agent that exhibits structural similarity and behavior akin to the latest generation of MDR1 inhibitors

Field-Portable Microplastic Sensing in Aqueous Environments: A Perspective on Emerging Techniques

Microplastics (MPs) have been found in aqueous environments ranging from rural ponds and lakes to the deep ocean. Despite the ubiquity of MPs, our ability to characterize MPs in the environment is limited by the lack of technologies for rapidly and accurately identifying and quantifying MPs. Although standards exist for MP sample collection and preparation, methods of MP analysis vary considerably and produce data with a broad range of data content and quality. The need for extensive analysis-specific sample preparation in current technology approaches has hindered the emergence of a single technique which can operate on aqueous samples in the field, rather than on dried laboratory preparations. In this perspective, we consider MP measurement technologies with a focus on both their eventual field-deployability and their respective data products (e.g., MP particle count, size, and/or polymer type). We present preliminary demonstrations of several prospective MP measurement techniques, with an eye towards developing a solution or solutions that can transition from the laboratory to the field. Specifically, experimental results are presented from multiple prototype systems that measure various physical properties of MPs: pyrolysis-differential mobility spectroscopy, short-wave infrared imaging, aqueous Nile Red labeling and counting, acoustophoresis, ultrasound, impedance spectroscopy, and dielectrophoresis