Fluphenazine, from the group of phenothiazines, is mainly known as a very potent antipsychotic drug [1]. Phenothiazines also belong to one of the eldest classes of modulators of multidrug resistance (MDR) in cancer cells. MDR is a development of the mechanism of active, outward drug transport, which is a common strategy used by cancer cells to defeat themselves against chemotherapeutic agents [2]. To obtain the accumulation of anticancer drugs in resistant cells either the permeability of the cell membrane must be increased or the efficiency of efflux pumps must be reduced. The direct relationship between membrane permeability and physical state of lipids is obvious, but also the activity of transporters should be modulated by the lipid composition [3] or biophysical properties (e.g. fluidity) of  the membrane [4].

To optimize and modulate the biological effects of fluphenazine some efforts are made to synthesize the derivatives of this phenothiazine. In the present work we studied the influence of fluphenazine itself and its new derivatives, synthesized in our department – SM1, SM8, SM10, SM12 – on lipid bilayers. Phenothiazine effects were assessed by spectrofluorimetry, using unilamellar liposomes labeled with DPH.

The studied phenothiazines  caused concentration-dependent increase of DPH fluorescence polarization anisotropy. The effect was observed for bilayers in  the liquid-crystalline phase, because liposomes were made of lecithin from egg yolk (EYPC), which is liquid at room temperature. The results presented allow the conclusion that studied phenothiazines interact with the lipid bilayers and decrease their fluidity in the liquid-crystalline phase. All of the studied compounds increased  DPH fluorescence polarization anisotropy in EYPC liposomes, which can be interpreted as a rigidifying effect exerted by this compound on the hydrocarbon chains regions of the lipid bilayer.

[1] M.J. Ohlow, B. Moosmann, Foundation review: Phenothiazine: the seven lives of pharmacology’s first lead structure, Drug Discovery Today 16, 3/4, (2011) 119–130,

[3] Y. Romsicki, F.J. Sharom, The membrane lipid environment modulates drug interactions with the P-glycoprotein multidrug transporter, Biochemistry 38 (1999) 6887–6896,

• Legal notice:
  

  Copyright (c) Pielaszek Research, all rights reserved.
  The above materials, including auxiliary resources, are subject to Publisher's copyright and the Author(s) intellectual rights. Without limiting Author(s) rights under respective Copyright Transfer Agreement, no part of the above documents may be reproduced without the express written permission of Pielaszek Research, the Publisher. Express permission from the Author(s) is required to use the above materials for academic purposes, such as lectures or scientific presentations.
  In every case, proper references including Author(s) name(s) and URL of this webpage: https://science24.com/paper/25473 must be provided.

1. Effect of the new derivatives of oxicams on efflux pumps overexpressed in resistant human colorectal adenocarcinoma cell line
2. Synthesis of new piroxicam derivatives and their influence on lipid bilayers
3. The interaction of new Piroxicam analogues with lipid bilayers – a calorimetric and fluorescence spectroscopic study
4. New Mannich bases of N-substituted 1H-pyrrolo[3,4-c]pyridine-1,3(2H)-diones and their biological properties
5. The interaction of new fluphenazine analogues with lipid membrane
6. New isothiazolopyridines and their in vitro antibacterial activity
7. Synthesis of N-substituted benzo-1,2-thiazine 1,1-dioxide derivatives with potential anti-inflammatory activity
8. PYRIDO-1,2-THIAZINES AND THEIR IN VITRO ANITBACTERIAL EVALUATION
9. A STRUCTURAL AND SAR STUDY OF 2-[4-(SUBSTITUTED-PHENYL)PIPERAZIN-1-YLMETHYL]ISOTHIAZOLO[5,4-b]PYRIDINES WITH ANALGESIC ACTIVITY.