A delineation of diketopiperazine self-assembly processes: Understanding the molecular events involved in N-epsilon-(Fumaroyl)diketopiperazine of L-Lys (FDKP) interactions
Abbreviated Journal Title
diketopiperazine; self-assembly; cooperative hydrogen bonding; lysine; DIAMIDE DIACIDS; CONFORMATION; BONDS; TAPES; WATER; NMR; IR; Medicine, Research & Experimental; Pharmacology & Pharmacy
The N-epsilon-fumaroylated diketopiperazine of L-Lys (FDKP, 1) self-assembles into microparticles that can be used for pulmonary drug delivery. When these particles are formulated with insulin, the resultant powder (Technosphere Insulin) provides a novel prandial insulin therapy. To better understand the self-assembly of 1, a series of model compounds were synthesized that allowed for the determination of the preferred intramolecular hydrogen-bonding pattern of FDKP. Variable-temperature NMR (CDCl3) and FTIR studies of acyclic diamides (3-7a) and diketopiperazine models (7b-9d) revealed the preference of a 10-membered hydrogen bond between one of the diketopiperazine's amido NH and the appended fumaramido-carbonyl (assigned as a "type B" H bond). Molecular modeling studies identified a low energy conformer in the architecture of 1, which contains two N-epsilon-fumaroylated lysine side chains appended to the diketopiperazine core. The lowest energy form involved a "cooperative" hydrogen bond motif which involved only one of the diketopiperazine amides and had one "arm" involved in a type B motif and the other in a "type A" hydrogen bond (i.e., the fumaramidyl NH H-bonding to the diketopiperazine amide carbonyl). This cooperative hydrogen bond scenario orients the appended fumaryl groups into a distinctive 90 degrees arrangement and is likely involved in its self-assembly into microparticles.
"A delineation of diketopiperazine self-assembly processes: Understanding the molecular events involved in N-epsilon-(Fumaroyl)diketopiperazine of L-Lys (FDKP) interactions" (2008). Faculty Bibliography 2000s. 527.