Anthracene-containing tetralactam macrocycles are prepared and found to have an extremely high affinity for squaraine dyes in chloroform (log Ka = 5.2). Simply mixing the two components produces highly fluorescent, near-infrared inclusion complexes in quantitative yield. An X-ray crystal structure shows the expected hydrogen bonding between the squaraine oxygens and the macrocycle amide NH residues, and a high degree of cofacial aromatic stacking. The kinetics and thermodynamics of the assembly process are very sensitive to small structural changes in the binding partners. For example, a macrocycle containing two isophthalamide units associates with the squaraine dye in chloroform 400,000 times faster than an analogous macrocycle containing two 2,6-dicarboxamidopyridine units. Squaraine encapsulation also occurs in highly competitive media such as mixed aqueous/organic solutions, vesicle membranes, and the organelles within living cells. The highly fluorescent inclusion complexes possess emergent properties; that is, as compared to the building blocks, the complexes have improved chemical stabilities, red-shifted absorption/emission maxima, and different cell localization propensities. These are useful properties for new classes of near-infrared fluorescent imaging probes.
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...
Molecular probes with zinc(II)-(2,2'-dipicolylamine) coordination complexes associate with oxyanions in aqueous solution and target biomembranes that contain anionic phospholipids. This study examines a new series of coordination complexes with 2,6-bis(zinc(II)-dipicolylamine) phenoxide as the molecular recognition unit. Two lipophilic analogues are observed to partition into the membranes of zwitterionic and anionic vesicles and induce the transport of phospholipids and hydrophilic anions (carboxyfluorescein). These lipophilic zinc complexes are moderately toxic to mammalian cells. A more hydrophilic analogue does not exhibit mammalian cell toxicity (LD 50 >50 µg/mL), but it is highly active against the Gram-positive bacteria Staphylococcus aureus (MIC of 1 µg/mL). Furthermore, it is active against clinically important S. aureus strains that are resistant to various antibiotics including vancomycin and oxacillin. The antibiotic action is attributed to its ability to depolarize the bacterial cell membrane. The intense bacterial staining exhibited by a fluorescent conjugate suggests that this family of zinc coordination complexes can be used as molecular probes for the detection and imaging of bacteria.
[reaction: see text] Tyrosine-derived Zn(2+) coordination complexes and their fluorescent NBD conjugates are synthesized in a short, high-yielding procedure. The Zn(2+) complexes are highly water soluble, but in the presence of sodium laurate they readily transfer into an octanol layer. Furthermore, the NBD-labeled bis-Zn(2+) complex can partition into vesicle membranes containing anionic phospholipids.
The appearance of anionic phosphatidylserine (PS) in the outer monolayer of the plasma membrane is a universal indicator of the early/intermediate stages of cell apoptosis. The most common method of detecting PS on a cell surface is to use the protein annexin V; however, in certain applications there is a need for alternative reagents. Recent research indicates that rationally designed zinc 2,2'-dipicolylamine (Zn2+-DPA) coordination complexes can mimic the apoptosis sensing function of annexin V. Here, a series of fluorescently-labelled, tri- and pentapeptides with side chains containing Zn2+-DPA are prepared and shown to selectively bind to anionic vesicle membranes. Fluorescein-labelled versions of the peptides are used to detect apoptotic cells by fluorescence microscopy and flow cytometry.
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