Date of Award
5-1-2026
Document Type
Dissertation
Degree Name
Ph.D. in Pharmaceutical Sciences
First Advisor
David A. Colby
Second Advisor
John M. Rimoldi
Third Advisor
Hailiang J. Zhu
School
University of Mississippi
Relational Format
dissertation/thesis
Abstract
Fluorinated organic molecules have become increasingly valuable in medicinal chemistry, with approximately 20–25% of FDA-approved drugs containing at least one fluorine atom. Among fluorinated motifs, the hexafluoroisopropanol (HFIP) group stands out for its unique combination of high level of fluorination with the adjacent alcohol functionality, which offers strong hydrogen bond donation with minimal nucleophilicity. Recent studies highlight HFIP as a promising building block for the development of drug-like molecules, including antibody–drug conjugates (ADCs), which is a novel class of targeted chemotherapeutics that link monoclonal antibodies with potent cytotoxic agents. However, ADC can exhibit substantial toxicity owing to their susceptibility to off-target payload release, thereby limiting the therapeutic potential of ADC in cancer treatment. Therefore, we envisioned that incorporation of the HFIP group could facilitate bioanalytical studies through 19F-NMR tagging. This strategy enables the monitoring of drug release from ADCs and offers a means to mitigate associated toxicities. Despite its values in medicinal chemistry, synthetic methods for incorporating HFIP into molecules remain limited and are hindered by many deficiencies. In this study, we discovered that amine salts which contain hexafluoroacetone hydrate can be used for the synthesis of HFIP derivatives from anilines and indoles. This method eliminates the reliance on moisture-sensitive reagent or the use of large quantity of HFIP as a solvent. We also developed a new reagent that integrates the ligand bipyridine, a common additive in many organometallic reactions. This novel reagent can be easily synthesized, which serve as a stable and valuable hydroxyfluoroalkylating reagent for indoles providing up to 98% in yield. Building upon this project, we designed synthetic schemes to generate HFIP-tagged molecules as models that mimic structural features of ADCs. The models will serve as a prodrugs in which the HFIP is essential to verify the delivery and fragmentation of the active drug. We anticipate that our methods and technique will advance fluorine-containing drug design and contribute to the development of novel therapeutic modalities.
Recommended Citation
Alghamdi, Meshal, "Synthesis of Hexafluoroisopropanols as Building Blocks for Fluorine-Tagged Molecules" (2026). Electronic Theses and Dissertations. 8791.
https://egrove.olemiss.edu/etd/8791