A delineation of diketopiperazine self-assembly processes: Understanding the molecular events involved in N-epsilon-(Fumaroyl)diketopiperazine of L-Lys (FDKP) interactions

    Authors

    N. Kaur; B. Zhou; F. Breitbeil; K. Hardy; K. S. Kraft; I. Trantcheva;O. Phanstiel

    Comments

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    Abbreviated Journal Title

    Mol. Pharm.

    Keywords

    diketopiperazine; self-assembly; cooperative hydrogen bonding; lysine; DIAMIDE DIACIDS; CONFORMATION; BONDS; TAPES; WATER; NMR; IR; Medicine, Research & Experimental; Pharmacology & Pharmacy

    Abstract

    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.

    Journal Title

    Molecular Pharmaceutics

    Volume

    5

    Issue/Number

    2

    Publication Date

    1-1-2008

    Document Type

    Article

    Language

    English

    First Page

    294

    Last Page

    315

    WOS Identifier

    WOS:000254708600012

    ISSN

    1543-8384

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