| Abstract | Increasingly, pharmaceutical companies focus on developing orally available drugs because they offer ease of administration and improve patient compliance. A drug achieves oral availability by possessing a hydrophilic and a hydrophobic component, allowing it to partition across the membrane. A key parameter for evaluating the oral availability, logP, is determined by the compound?s partitioning between oil and water, typically measured using RP-HPLC. Orally available drugs have a logP between -0.4 and 5. Towards this goal, we explored the possibility of tuning logP values by modulating the structure of the synthetic macrocycles.
This thesis explores the syntheses of 24-atom macrocycles with contrasting polarities as a potential model for developing orally available drugs. A three-step process is employed to make macrocycles. First, cyanuric chloride is sequentially substituted with BOC-hydrazine, then an amino acid, and finally, dimethylamine, to yield X-acid, where X represents an amino acid. Next, an acetal group is added to form the monomer, X-M. Under acidic conditions, hydrogen bonding templates the dimerization of two monomers, forming the macrocycle X-X.
The macrocycle achieves differing polarities by incorporating various amino acids into the scaffolds. The hydrophobic component of the heterodimer is achieved with 2-aminooctanoic acid (OA), characterized by its long hydrocarbon chain, while serine and lysine represent the hydrophilic component. NMR spectroscopy distinguishes and analyzes the new resonances of the heterodimers OA-K and OA-S. The polarity of the heterodimers was analyzed with RP-HPLC and TLC and compared to the corresponding homodimers. The conclusion of this work is that the logP of macrocycles can be tuned through the synthesis of heterodimers. |
