Text

theses

Amphiphilic molecules are comprised of hydrophobic and hydrophilic domains. These molecules possess diverse chemical structures, which govern their physicochemical and biological properties, and these properties dictate amphiphiles’ use in various applications. This dissertation focuses on the design, synthesis, and characterization of amphiphiles for biomedical applications. Amphiphilic macromolecules (AMs), comprised of an acylated sugar backbone conjugated to a hydrophilic poly(ethylene glycol), were investigated as atherosclerosis treatments. Atherosclerosis is characterized by the accumulation and macrophage-mediated uptake of oxidized low-density lipoprotein (oxLDL). Previous studies indicate that AMs competitively inhibit oxLDL uptake through interacting with macrophage scavenger receptors, which contain hydrophobic and/or basic residues near their binding domains. Using knowledge of scavenger receptor binding domains, two AM series – termed ether- and alkyl-AMs – were designed to elucidate whether hydrogen-bonding or hydrophobic-hydrophobic interactions more significantly influenced bioactivity, respectively. Upon successful synthesis of each series, AM physicochemical and biological properties were assessed. More hydrophobic AMs, possessing longer and/or alkyl-terminated (i.e., alkyl-AMs) acyl arms, exhibited enhanced oxLDL uptake inhibition and thus improved bioactivity. These studies demonstrated that hydrophobic interactions significantly influence anti-atherosclerotic activity. Biscationic tartaric acid-based amphiphiles were also investigated for antimicrobial applications. Cationic amphiphiles exhibit unique membrane-disrupting bactericidal mechanisms via a combination of electrostatic and hydrophobic-hydrophobic interactions. This work explored the specific impact of charge location on cationic amphiphiles’ antimicrobial and membrane activity. Two series of analogous cationic amphiphiles were synthesized, termed gemini-like and bola-like, which differed only in their charge location. After successful synthesis, antimicrobial activity was assessed and lead compounds identified. Bola-like amphiphiles exhibited preferential activity against gram-positive bacteria, while gemini-like amphiphiles were more active against gram-negative bacteria. Biophysical experiments indicated that the lead gemini-like amphiphile interacted with model membranes via electrostatic interactions, whereas the lead bola-like amphiphile relied on a combination of electrostatic and hydrophobic interactions. These studies demonstrate the significant influence of charge location on cationic amphiphile antimicrobial and membrane activity.

ETD_6458

Ph.D.

Includes bibliographical references

by Allison Marie Faig

doi:10.7282/T3PV6NC0

ETD doctoral

The author owns the copyright to this work.