pH- Triggered Dynamic Molecular Tweezers for Drug Delivery Applications

Abstract

My MSc project aims at developing pH-responsive molecular tweezers for drug delivery applications. The project began with the synthesis of our 2nd generation tweezer, whose main objective was to improve our previous model, 1st generation tweezer, which contained a pH-responsive triad spacer and two naphthalene walls known to interact with hydrophobic drugs such as Mitoxantrone®. The naphthalene interaction sites were successfully modified to contain oligoethylene glycol chains to improve their water-solubility, in anticipation for more accurate measurements of pKa and binding constants in aqueous media. However, all attempts to convert such naphthalene derivatives into their corresponding boronic acid or ester through standard protocols (halogen-lithium exchange, palladium catalyzed borylation) failed. Without the required boronic acid/ester, the final Suzuki-Miyaura coupling with the di-bromo triad spacer was not achieved. Synthesis of the 3rd generation tweezer, which was modified to contain theophylline as the new interaction sites, was then attempted. The half-tweezer was successfully synthesized via copper (II) catalyzed coupling of theophylline with the 5-bromo-4-methoxyphenyl boronic acid. However, all attempts to convert it into the required boronic acid/ ester for the final Suzuki- Miyaura coupling reaction with 2,6-dibromopyridine failed. We then focused our attention on the conversion of the triad spacer into its corresponding diboronic acid. The synthesis of the triad diboronic acid was a success, however, the final copper (II) catalyzed reaction with theophylline to form the tweezer only yielded the mono-coupled product. Lastly, our 4th generation tweezer was engineered to avoid the synthetic difficulties encountered in the boronic acid/ ester synthesis stage. Using the commercially available 5-formyl-2-methoxyphenylboronic acid and o-phenylenediamine, we successfully synthesized a benzimidazole-derived “half tweezer” through ring condensation reaction. Alkylation of this half-tweezer was also successfully achieved, although purification of the alkylated product was not optimized. Using this crude product, we carried out the final tweezer reaction via Suzuki- Miyaura coupling with 2,6-dibromopyridine under microwave irradiation. 1H NMR results show formation of new species that is believed to be the 4th generation tweezer (although the presence of impurities made integration of the signals unreliable). Much work is needed in the purification of the alkylated half tweezer boronic acid in order to avoid complicated mixtures in the final tweezer reaction.