Fluphenazine: from an isolated molecule to its interaction with lipid bilayers.

Fluphenazine (FPh) belongs to the phenothiazine family of compounds and exhibits a wide variety of biological effects, including antimutagenic, proapoptotic, antiproliferative and anti-multidrug resistance (MDR) activities. The ability of FPh to interact with lipid membranes can have a significant impact on its biological activities. However, the mechanisms involved in the interaction of FPh with lipid membranes are poorly understood.

Synthesis, pro-apoptotic activity and 2D-QSAR studies of new analogues of fluphenazine.

A series of 10 novel analogues of fluphenazine (FPh) were synthesized. Influence of the synthesized analogues of FPh on frequency of apoptosis and necrosis in cultures of human lymphocytes genotoxically damaged in vitro with benzo[a]pyrene (B[a]P; 7,5 microM, 48 h) was compared with the effect of FPh. Activity of the tested compounds was expressed by ED50 (pro-apoptotic activity) and TD50 (pro-necrotic effect, cytotoxicity).

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

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.

Chemical structure of phenothiazines and their biological activity.

Phenothiazines belong to the oldest, synthetic antipsychotic drugs, which do not have their precursor in the world of natural compounds. Apart from their fundamental neuroleptic action connected with the dopaminergic receptors blockade, phenothiazine derivatives also exert diverse biological activities, which account for their cancer chemopreventive-effect, as: calmodulin- and protein kinase C inhibitory-actions, anti-proliferative effect, inhibition of P-glycoprotein transport function and reversion of multidrug resistance. According to literature data on relations between chemical structure of phenothiazines and their biological effects, the main directions for further chemical modifications have been established.

New fluphenazine analogues as inhibitors of P-glycoprotein in human lymphocyte cultures.

Aim Of The Study: To evaluate the inhibitory effect of 17 new analogues of FPh on the Pgp transport function, by estimation of the rhodamine 123 (Rod-123) accumulation inside cultured lymphocytes.

Material And Methods: Lymphocyte were cultured in the presence of a lectin (PHA; 2%, v/v), incubated with benzo[α]pyrene (B[α]P; 7.5 µM, 48 h) to induce genotoxic damage and to increase Pgp expression in the cells.

Interactions of dihydrochloride fluphenazine with DPPC liposomes: ATR-IR and 31P NMR studies.

The influence of dihydrochloride fluphenazine (FPh) on the dipalmitoylphosphatidylcholine (DPPC) bilayer structure was investigated using ATR-IR and (31)P NMR methods. The ATR-IR results indicate an increase in conformational disorder in the hydrophobic part compared with pure DPPC liposomes and a decrease in temperature of the chain-melting phase transition in FPh/DPPC liposomes. These effects depended on the concentration of the drug in the DPPC bilayer.

Antimutagenic activity of new analogues of fluphenazine.

Fluphenazine (FPh) exhibited antimutagenic activity in lymphocyte cultures, markedly decreasing genotoxic effects of standard mutagenic agents present in cell cultures. However, the strong pharmacological activity of this neuroleptic drug, together with its serious side effects on the central nervous system, limits its use as an antimutagenic compound. In this paper we describe a route of chemical synthesis of FPh analogues that are more hydrophilic than the model compound, thus probably penetrate more weakly through the blood-brain barrier.