Phosphatidylcholine-Derived Bolaamphiphiles via Click Chemistry

Abstract

The copper catalyzed azide alkyne cycloaddition is employed to modify phosphatidylcholine precursors with sn-2 acyl chains containing terminal alkyne or azide groups. Although the reactions are conducted as biphasic dispersions, the yields are essentially quantitative. Bolaamphiphiles are formed by simply clicking together two phosphatidylcholine alkyne precursors to a central bisazide scaffold. The chemistry introduces polar 1,4-triazole units into the lipophilic region of the bilayer membrane, and the bolaamphiphiles do not form stable vesicles.Bolaamphiphiles are amphiphilic compounds, containing two hydrophilic head-groups connected by a hydrophobic spacer. 1 One of the best-known families of naturally-occurring bolaamphiphiles are the archae lipids. A typical structure, shown in Figure 1, has a hydrocarbon chain that is connected by ether linkages to two zwitterionic phosphocholine head-groups. 2 These membrane-spanning, polar lipids rigidify the bilayer membrane and allow the thermophilic archae to endure temperatures in excess of 80° C and low pH. 3 Since it is difficult to produce these natural products in large amounts, several groups have investigated simplified synthetic mimics and found that they also have membrane stabilizing properties. Synthetic bolaamphiphiles with membrane-spanning macrocycles, 4 or unbranched hydrocarbon chains, 5 linking two phosphoglycerol head-groups are known to form membranes with increased melting temperatures, decreased permeation of ions and small polar molecules, and increased ordering of the membrane components. 7 Typically, these molecular designs incoporate polar functionality into the central region of a spacer that is otherwise hydrophobic. Whatever the specific functional objective, the bolaamphiphile synthesis is always a major technical challenge, especially if the molecule contains sensitive functionality such as that found in the head-groups of the common, naturally occurring, phospholipids.Our recent interest in the effects of bolaamphiphiles on membrane structure and function 8 has lead us to develop a method of producing them in large amounts from readily available starting materials. An obvious family of potential building blocks, that have pre-installed polar headgroups, are the lysophospholipids, with lysophophosphatidylcholine as the archetype example. Acylation of the sn-2 hydroxyl in lysophophosphatidylcholine with a suitably functionalized acyl chain gives a phosphatidylcholine precursor that can be dimerized to produce a bolaamphiphile. The chemistry to produce symmetric couplings includes olefin metathesis9 and Glaser oxidation;4a whereas, asymmetric cross couplings have been achieved using the Wittig reaction, nucleophilic substitution, conjugate addition, and the Diels-Alder reaction. 5c ,6 The latter reactions have also been conducted in preformed liposomal membranes. All of these synthetic procedures have drawbacks; either the yields are not extremely high or the chemistry is not compatible with all types of biomolecular functional gr...

Click Chemistry: 1,2,3‐Triazoles as Pharmacophores

“…The wide scope of CuAAC is firmly demonstrated by its use in different areas of life and material sciences such as drug discovery, [10] bioconjugation, [11] polymer and materials science, [12] and related areas [13] including supramolecular chemistry. [14] DNA labeling [15] and oligonucleotide synthesis, [16] assembly of glycoclusters [17] and glycodendrimers, [18] preparation of stationary phases for HPLC column, [19] development of microcontact printing, [20] conjugation of molecular cargos to the headgroup of phospholipids, [21] and construction of bolaamphiphilic structures [22] are further examples of the use of CuAAC.…”

Synthesis, surface properties, and biocompatibility of 1,2,3-triazole-containing alkyl β-d-xylopyranoside surfactants

“…This heterocycle has found widespread usage 9 in a broad range of disciplines such as medicinal chemistry and materials chemistry. The 1,2,3-triazole moiety has been found in bolaamphiphile, 10 star-like, 11 and fluorocarbon surfactants. 12-13 While both xylose head groups and 1,2,3-triazoles have been used in surfactants, the two have not been used in combination.…”

Fluorescent labeling of alkyl chains of phosphocholine lipids by one-pot TMS cleavage-click reaction

“…The coupling reaction 1 + 3 takes place with good yield in such a mild conditions that protection of the phosphocholine group is not required, as noted previously [20]. In this regard, click conjugation compares very favorably with the step-by-step synthesis of fluorescent miltefosine analogs described before [2d].…”