A Delineation of Diketopiperazine Self-Assembly Processes: Understanding the Molecular Events Involved in N^ϵ-(Fumaroyl)diketopiperazine of l-Lys (FDKP) Interactions

Abstract

The Nepsilon-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 Nepsilon-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.

Development and evaluation of cationic amphiphilic antimicrobial 2,5‐diketopiperazines

“…The protected compound was deprotonated with NaH and further alkylated with benzyl bromide . Deprotection of the Z groups was carried out via hydrogenation, and the amine was converted to its corresponding hydrochloride salt to afford 11 . Alkylation of 10 with 4‐phenylbenzyl bromide followed by deprotection gave 12 .…”

An improved synthesis of a fluorophosphonate–polyethylene glycol–biotin probe and its use against competitive substrates

“…tert -Butyl (5-(5-((3a S ,4 S ,6a R )-2-oxohexahydro-1 H -thieno[3,4- d ]imidazol-4-yl)pentanamido)pentyl)carbamate (11): This compound was made by the procedure of Konoki et al [18] from tert -butyl (5-aminopentyl)carbamate ( 10 ; made by the procedure of Kaur et al [25]) and D-biotin. The 1 H NMR spectrum is the same as previously reported [18]; 13 C NMR (125 MHz, CDCl 3 ) δ 173.3, 164.2, 156.2, 79.1, 61.8, 60.2, 55.8, 40.5, 40.3, 39.2, 36.0, 29.7, 29.1, 28.4, 28.2, 28.0, 25.8, 23.9; MS m / z : 451.1 [M + Na] + .…”

An Albumin-Derived Peptide Scaffold Capable of Binding and Catalysis

“…This compound was then coupled with N-Boc-1,5-diaminopentane [45] to give tert -butyl-5-(2-(( R )-6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-2-oxo-2 H -benzo[ d ] [1], [3]oxazin-1(4 H )-yl)acetamido)pentylcarbamate: the acid analogue of efavirenz (190 mg, 0.51 mmol)) was stirred in dry CH 3 CN (3.4 mL) under argon atmosphere conditions. HOBt (69 mg, 0.51 mmol) and NMM (about 112 µL, 1.02 mmol) were added maintaining pH at 8–8.5.…”