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

Imaging Cellular Distribution of Bcl Inhibitors Using Small Molecule Drug Conjugates

Overexpression of anti-apoptotic proteins such as Bcl-2 is a cellular mechanism to evade apoptosis; consequently, Bcl-2 inhibitors are being developed as anticancer agents. In this work, we have synthesized a fluorescent version of ABT-199 in an effort to visualize a drug surrogate by high resolution imaging. We show that this fluorescent conjugate has comparable Bcl-2 binding efficacy and cell line potency to the parent compound and can be used as an imaging agent in several cancer cell types. We anticipate that this agent will be a valuable tool for studying the single-cell distribution and pharmacokinetics of ABT-199 as well the broader group of BH3-mimetics

Effects of traditional swaddling on development: a randomized controlled trial.

OBJECTIVE: Evidence of the effects of tight, prolonged binding of infants on development is inconclusive and based on small ethnographic studies. The null hypothesis was that Mongolian infants not swaddled or swaddled tightly in a traditional setting (to >7 months of age) do not have significantly different scores for the Bayley Scales of Infant Development, Second Edition (BSID-II). PATIENTS AND METHODS: In a randomized controlled trial, 1279 healthy newborns in Ulaanbaatar, Mongolia, were allocated at birth to traditional swaddling or nonswaddling. The families received 7 months of home visits to collect data and monitor compliance. At 11 to 17 months of age, the BSID-II was administered to 1100 children. RESULTS: No significant between-group differences were found in mean scaled mental and psychomotor developmental scores. The unadjusted mean difference between the groups was -0.69 (95% confidence interval [CI]: -2.59 to 1.19) for psychomotor and -0.42 (95% CI: -1.68 to 0.84) for mental scores in favor of the swaddling group. A subgroup analysis of the compliant sample produced similar results. BSID-II-scaled psychomotor and mental scores were 99.98 (95% CI: 99.03-100.92) and 105.52 (95% CI: 104.89-106.14), respectively. Background characteristics were balanced across the groups. CONCLUSIONS: In the Mongolian context, prolonged swaddling in the first year of life did not have any significant impact on children's early mental or psychomotor development. Additional studies in other settings need to confirm this finding. The Mongolian infants in this trial had scaled BSID-II mental and psychomotor scores comparable to United States norms