Cationic domain formation

For the medicinal chemist it is of interest to note that such phenomena, i.e. phase separation and domain formation, can also be induced in artificial membranes by cationic amphiphilic drugs. An increase in the microheterogeneity of biological membranes and in consequence a decisive change in membrane function in a defined area must, therefore, be considered. It is mediated through indirect physicochemical interaction with amphiphilic drags. 

The entrapping of water-soluble compounds in the small internal water volume and their release within a period of several minutes or hours is evidently a relatively simple task as was demonstrated with the preceding examples. No domain formation or perforation is necessary here. Small cations, however, were only released in under a day in the case where the membrane was perforated or contained a dissolved carrier system. Before turning to these systems, we shall firstly introduce synkinetic domains. 

H solid-state NMR was employed to critically examine domain formation in bacteria-mimetic membranes due to cationic peptide binding. The results provide insight into the extent of domain formation in bacterial membranes and the possible peptide structural requirements for this phenomenon. ... 

Kwon et al. used NMR to investigate domain formation in membranes (phosphatidylethanolamine (POPE) and anionic l-palmitoyl-2-oleoyl-s -gZycero-3-phosphatidylglycerol (POPG)) with to cationic peptides. The antimicrobial peptides were (AMP(3)) of the beta-hairpin family of protegrin-1 (PG-1), and two cell-penetrating peptides (CPPs), HIV TAT and penetratin. The NMR showed the extent of the interaction between the bilayers and the peptides. 

As a further mechanism, electrostatic interactions of anionic lipids with cationic compounds may also induce domain formation. Due to the biochemical complexity of biological membranes, the molecular mechanisms responsible for phase separation are not easily distinguished experimentally. 

The second mode of toxicity is postulated to involve the direct interaction of the epidithiodiketopiperazine motif with target proteins, forming mixed disulfides with cysteine residues in various proteins. Gliotoxin, for example, has been demonstrated to form a 1 1 covalent complex with alcohol dehydrogenase [13b, 17]. Epidithiodi-ketopiperazines can also catalyze the formation of disulfide bonds between proxi-mally located cysteine residues in proteins such as in creatine kinase [18]. Recently, epidithiodiketopiperazines have also been implicated in a zinc ejection mechanism, whereby the epidisulfide can shuffle disulfide bonds in the CHI domain of proteins, coordinate to the zinc atoms that are essential to the tertiary structure of that domain, and remove the metal cation [12d, 19],... 

A systematic carbocation concentration dependency study on NMR chemical shifts was performed for the C-l-protonated 477-cyclopenta[fi e/ phenanthrenium cation 7H+ and the C-l-protonated pyrenium cation 2H+ (Fig. 11). Shielding of the PAH arenium ion protons and carbons was observed with decreasing FSO3H PAH ratios without noticeable line-broadening. This was attributed to cation-anion interactions in the low FSO3H PAH domain and possible formation of contact ion... 

Many reports are available where the cationic surfactant CTAB has been used to prepare gold nanoparticles [127-129]. Giustini et al. [130] have characterized the quaternary w/o micro emulsion of CTAB/n-pentanol/ n-hexane/water. Some salient features of CTAB/co-surfactant/alkane/water system are (1) formation of nearly spherical droplets in the L2 region (a liquid isotropic phase formed by disconnected aqueous domains dispersed in a continuous organic bulk) stabilized by a surfactant/co-surfactant interfacial film. (2) With an increase in water content, L2 is followed up to the water solubilization failure, without any transition to bicontinuous structure, and (3) at low Wo, the droplet radius is smaller than R° (spontaneous radius of curvature of the interfacial film) but when the droplet radius tends to become larger than R° (i.e., increasing Wo), the microemulsion phase separates into a Winsor II system. 

Independent of the assumptions A to C the cation selectivity of the membranes in the equilibrium domain is therefore controlled by the ratio of the complex formation constants (6) and should therefore be identical for different types of neutral carrier membranes.18 Figure 2 indicates that there is indeed a close parallelism between the selectivities of solvent polymeric membranes (SPM) and bilayer lipid membranes (BLM) modified with valinomycin 1, nonactin 2, trinactin 5, and tetranac-tin 6 (see also Ref. 18). This is in good agreement with findings from Eisenman s45 and Lev s15 research groups. 

---