General Synthesis and Physicochemical Characterisation of a Series of Peptide‐Mimic Lysine‐Based Amino‐Functionalised Lipids

Abstract

A series of novel malonic acid diamides (second generation) with two long hydrophobic alkyl chains and an alkaline polar head group was synthesised and characterised as a new class of amino-functionalised lipids. These peptide-mimic lipids are suitable for polynucleotide transfer. The lipids bear a novel backbone consisting of a lysine unit and a malonic acid unit. Six different head-group structures, which vary in size and number of amino groups that can be protonated, were attached to the backbone structure. Furthermore, different alkyl chains were used to build the lipophilic part (namely tetradecyl, hexadecyl, and oleyl). Phase transitions of the new compounds in aqueous dispersions at pH 10 were analysed and discussed in terms of head group and alkyl chain variations. The shape and size of the formed aggregates of selected lipid dispersions were investigated by dynamic light scattering and transmission electron microscopy.

Composites of malonic acid diamides and phospholipids – Structural parameters for optimal transfection efficiency in A549 cells

“…Phosphate buffered saline (PBS) was purchased from Sigma Aldrich (Steinheim, Germany). The synthesis of TH4 ( N ‐[6‐amino‐1‐oxo‐1‐( N ‐tetradecylamino)hexan‐(2 S )‐2‐yl]‐ N ′‐{2‐[ N , N‐ bis(2‐aminoethyl)amino]ethyl}‐2‐hexadecylpropandiamide) is described in the literature . OH4 ( N ‐{6‐amino‐1‐[ N ‐(9 Z )‐octadec‐9‐enylamino]‐1‐oxohexan‐(2 S )‐2‐yl}‐ N ′‐{2‐[ N , N ‐bis(2‐aminoethyl)amino]ethyl}‐2‐hexadecylpropandiamide) was synthesized using the same procedures.…”

“…Recently, we have reported the synthesis of a new class of amino functionalized lipids for the use as gene transferring agents, called the second generation of malonic acid diamides . In the present work, we will focus on the evaluation of the in vitro transfection efficacy of two representatives of this new class of cationic lipids.…”

Lamellar versus Micellar Structures—Aggregation Behavior of a Three‐Chain Cationic Lipid Designed for Nonviral Polynucleotide Transfer

“…The lipid used in this work belongs to the class of malonic acid diamideso ft he second generation described previously. [15][16][17] The lipid was synthesized from precursor A, precursor B, and tris(2-aminoethyl)amine using synthesisp rocedures described earlier( Scheme 1). [17] DiTT4 has three alkyl chains (lipophilic moieties).…”

“…[15][16][17] The lipid was synthesized from precursor A, precursor B, and tris(2-aminoethyl)amine using synthesisp rocedures described earlier( Scheme 1). [17] DiTT4 has three alkyl chains (lipophilic moieties). One is bounda tt he lysine unit of the backbone and two are substituted at the a-carbon atom of the malonic acid diamide unit.…”

“…Cell culture medium and fetal bovine serum were supplied from PAAL aboratories GmbH (Cçlbe, Germany). N-[6-Amino-1-oxo-1-(N-tetradecylamino)hexan-(2S)-2-yl]-N'-{2-[N,N-bis(2-aminoethyl)amino]ethyl}-2,2-ditetradecylpropandiamide (DiTT4) was synthesized according to published methods with (2S)-2-amino-6-[(tert-butoxycarbonyl)]amino-N-tetradecylhexanamide (precursor A) [17] and ditetradecylmalonic acid monoethyl ester (precursor B) as the main intermediates. [17] Analytical data are summarized in the Supporting Information.…”