Phase separation in phosphatidylcholine membrane caused by the presence of a pyrimidine analogue of fluphenazine with high anti-multidrug-resistance activity.

Abstract

Phenothiazine compounds are known as effective inhibitors of a multidrug resistance (MDR) of tumor cells to chemotherapeutic agents. This group consists of many important substances used in human medicine such as antipsychotic drugs in the case of fluphenazine (FPh) or chlorpromazine (CPZ). Fluphenazine was on the World Health Organization (WHO) list of Essential Medicines of 2009, and its new pyrimidine analog (FPh-prm) presented in this work has been documented to have a high anti-MDR activity. In order to discover the character of alterations of the lipid bilayer structure caused by the presence of FPh-prm inside the lipid membrane, which is responsible for the essential increase of an anti-MDR activity of FPh-prm, microcalorimetric (differential scanning calorimetry), Laurdan fluorescence, (31)P nuclear magnetic resonance spectroscopy (NMR), and attenuated total reflectance Fourier transfer infrared spectroscopy (FTIR-ATR) were used for dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) liposomes mixed with a different concentration of amine analogue. It was stated that the formation of domains with different content of FPh-prm/DPPC can be a reason for the membrane-related mechanism of chemoprevention associated with the inhibition of the outward transport of anticancer drugs by the glycoprotein P (Pgp) in cancer cells by the pyrimidine analog of FPh. To our best knowledge, this report is the first to show the bilayer structure of domains formed by incomplete miscibility of fluphenazine-related compounds and phospholipid molecules. Our results provide a sound basis for the design of future modifications of anti-MDR drugs by providing very effective inhibitors of the pump activity of Pgp.

• Authors: Katarzyna Cieślik-Boczula, Piotr Swiątek, Agata Jaszczyszyn, Patrycja Zawilska, Kazimierz Gąsiorowski, Wiesław Malinka, Gottfried Köhler
• Journal: The journal of physical chemistry. B (J Phys Chem B) Vol. 118 Issue 13 Pg. 3605-15 (Apr 03 2014) ISSN: 1520-5207 [Electronic] United States
• PMID: 24601791 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antineoplastic Agents
• Antipsychotic Agents
• Lipid Bilayers
• Liposomes
• Phosphatidylcholines
• Pyrimidines
• 1,2-Dipalmitoylphosphatidylcholine
• Phosphorus
• Fluphenazine

Topics

• 1,2-Dipalmitoylphosphatidylcholine (chemistry)
• ATP Binding Cassette Transporter, Subfamily B, Member 1 (chemistry, metabolism)
• Antineoplastic Agents (chemistry)
• Antipsychotic Agents (chemistry)
• Calorimetry, Differential Scanning
• Drug Resistance, Multiple
• Fluphenazine (chemical synthesis, chemistry)
• Humans
• Lipid Bilayers (chemistry)
• Liposomes (chemistry)
• Magnetic Resonance Spectroscopy
• Phosphatidylcholines (chemistry)
• Phosphorus (chemistry)
• Pyrimidines (chemistry)
• Spectroscopy, Fourier Transform Infrared