Interaction of Phenothiazine Compounds with Zwitterionic Lysophosphatidylcholine Micelles:  Small Angle X-ray Scattering, Electronic Absorption Spectroscopy, and Theoretical Calculations

Abstract

In this work, small-angle X-ray scattering (SAXS) studies on the interaction of the phenothiazine cationic compounds trifluoperazine (TFP, 2-10 mM) and chlorpromazine (CPZ, 2-10 mM) with micelles of the zwitterionic surfactant L-R-lysophosphatidylcholine (LPC, 30 mM), at pHs 4.0 and 7.0, are reported. The SAXS results demonstrate that, upon addition of both phenothiazines, the LPC micelle of prolate ellipsoidal shape changes into a cylindrically shaped micelle, increasing its axial ratio from 1.6 ( 0.1 (in the absence of drug) to 2.5 ( 0.1 (for 5 and 10 mM of phenothiazine). Such an effect is accompanied by a shrinking of the paraffinic shortest semiaxis from 22.5 ( 0.3 to 20.0 ( 0.5 Å. Besides, a significant increase in polar shell electron density from 0.39(1) to 0.45(1) e/Å 3 is observed, consistent with cylinder-like aggregate geometry. Moreover, an increase of the phenothiazine concentration induces the appearance of a repulsive interference function over the SAXS curve of zwitterionic micelles, which is typical of interaction between surfacecharged micelles. Such a finding provides evidence that the positively charged phenothiazine molecule must be accommodated near the hydrophobic/hydrophilic inner micellar interface in such a way that a net surface charge is altered with respect to the original overall neutral zwitterionic micelle. Such phenothiazine location is favored by both electrostatic and hydrophobic contributions, giving rise to binding constant values, obtained from electronic absorption results, that are quite larger compared to their binding to another zwitterionic surfactant, 3-(N-hexadecyl-N,N-dimethylammonio)propanesulfonate (HPS) (Caetano, W., et al. J. Colloid Int. Sci. 2003, 260, 414-422). Comparisons are made by means of theoretical calculations of the surfactant headgroup dipole moments for monomers of LPC and HPS. The theoretical results show that the dipole moment in LPC is almost perpendicular to the methylene chain, while a significant contribution along the methylene chain occurs for HPS. Besides, evidence is presented for extensive delocalization of the charges in the headgroups, which could be also relevant for the binding of the drugs.

Interaction of meso-tetrakis (4-sulfonatophenyl) porphyrin with cationic CTAC micelles investigated by small angle X-ray scattering (SAXS) and electron paramagnetic resonance (EPR)

“…Altogether, these findings denote that the porphyrin location is favored by both electrostatic and hydrophobic contributions, giving rise to binding constant values that are quite larger as compared to the binding of cationic drugs to HPS micelles [13]. Similar results were also recently obtained for the interaction between cationic phenothiazine drugs and zwitterionic lysophosphatidylcholine (LPC) micelles, noting that the dipole moment component along the methylene chain for HPS and LPC molecules differs significantly in the magnitude and sense [14].…”

“…In a previous study [23], we have reported a similar behavior for SAXS curve from 40 mM of pure SDS micelles at pH 4.0, where a narrow peak at q = 0.04 Å −1 was observed. In the case of 30 mM of both drug-free HPS and LPC micelles [12,14], the SAXS curves were fitted by considering S(q) = 1 in Eq. (1), consistent with the noninteracting zwitterionic micelles due to their null overall charge.…”

The Role of the Membrane Actions of Phenothiazines and Flavonoids as Functional Modulators

“…In conclusion, the results of all studies on CPZ (9) and TFP (5) binding to detergent micelles pointed to such a localization of drug molecules in the micelle that the protonated phenothiazine side group was placed near the polar head region of detergent molecules, whereas the hydrophobic ring system was immersed in the interior of the micelle [26].…”

“…The interaction of two phenothiazines, TFP (5) and CPZ (9), with detergent micelles of different character was thoroughly investigated [22][23][24][25][26]. First, the binding of 5 and 9 to cationic, zwitterionic, and neutral detergent micelles was studied by means of absorption spectroscopy [22].…”

“…Such drug-associated transitions were not observed for micelles of zwitterionic detergent 3-(N-hexadecyl-N,Ndimethylammonio)propanesulfonate (HPS). However, later studies where another zwitterionic detergent-lysophosphatidylcholine (LPC)-was used demonstrated that binding of CPZ (9) and TFP (5) caused the micelles' shape to change from ellipsoid to cylindrical in this system, too [26]. Additionally, the LPC micelles gained a non-null overall surface micelle charge in the presence of phenothiazines.…”