Title

A Delineation Of Diketopiperazine Self-Assembly Processes: Understanding The Molecular Events Involved In NΕ-(Fumaroyl)Diketopiperazine Of L-Lys (Fdkp) Interactions

Keywords

Cooperative hydrogen bonding; Diketopiperazine; Lysine; Self-assembly

Abstract

The Nε-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 Nε- 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°arrangement and is likely involved in its self-assembly into microparticles. © 2008 American Chemical Society.

Publication Date

3-1-2008

Publication Title

Molecular Pharmaceutics

Volume

5

Issue

2

Number of Pages

294-315

Document Type

Article

Personal Identifier

scopus

DOI Link

https://doi.org/10.1021/mp700096e

Socpus ID

42549115888 (Scopus)

Source API URL

https://api.elsevier.com/content/abstract/scopus_id/42549115888

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