Interaction of protonated anticancer thiazines with water-insoluble phospholipids and antineoplastic agents

A series of neuroleptic protonated phenothiazine derivatives (promethazine, promazine, triflupromazine, methotrimeprazine, propiomazine, trifluoperazine and fluphenazine), some with known anticancer properties, were complexed with water-insoluble antineoplastice agents such as 5-fluorouracil (5FU), methotrexate (MTX) and sulindac, as well as with components of biomembrane and synthetic phospholipids as possible models of cancer and microbial cells. In all cases water-soluble micellar inclusion adducts were formed exhibiting electron charge transfer complex behaviour, with the appearance of thazine free radicals. The thiazines sequestered the drugs and phospholipids in well-defined molar ratios (MR) parabolically-dependent on the dipole moments (mu) of the protonated phenothiazine derivatives. pH comparisons showed that the inclusion adducts followed a model in which the compounds were enveloped in the lipophilic interior of the thiazine aggregates, while the side-chains of the latter faced the aqueous environment. In the model experiment, interaction of the thiazines and the 5FU adducts with E. coli F' lac was additive to marginally synergistic, confirmed by the checkerboard technique. The parabolic dependence of the molar minimum inhibitory concentration of the thiazines and thiazine/5FU adducts on the thiazine dipole moments suggests that their primary loci of interaction are the cell wall or membrane phospholipid components. Thiazines, especially those with dipole moments centered on about 6 D, near which the lowest MR occurs, can act as effective carriers for insoluble or sparsely soluble drugs. Any new thiazine drug for use alone or as a carrier in anticancer therapy should be designed with this criterion in mind.