Enhancement of drug affinity for cell membranes by conjugation with lipoamino acids. I. Synthesis and biological evaluation of lipophilic conjugates of tranylcypromine.

Conjugation with lipoamino acids (LAAs) increases the lipophilicity of drug molecules. Because of their amphipatic nature, they also provide the conjugated drugs a 'membrane-like character', capable to facilitate their interaction with and penetration through cell membranes and biological barriers. To study such a feature, our aim is to collect experimental and computational data using a novel series of lipophilic conjugates between a model drug (tranylcypromine (TCP)) and LAA residues containing a short, a medium or a long alkyl side chain (C-4 to C-16), to provide a wide range of lipophilicity. For comparison, a corresponding set of amides of TCP with alkanoic or fatty acids was prepared and characterized. Their in vitro monoamine oxidase inhibitory activity also tested.

Effect of liposomal delivery on in vitro antitumor activity of lipophilic conjugates of methotrexate with lipoamino acids.

Some selected lipophilic conjugates of the antifolate drug methotrexate (MTX) with lipoamino acids (LAA), previously described, were incorporated in liposomes with a different composition and charge (neutral, positive, or negative). The properties of the liposomal systems were determined. The inhibitory activity of the conjugates after incorporation in the vesicles was determined in a preliminary assessment against a human erythroleukemic cell line (K562 cells) and compared with the activity of the parent drug and of free conjugates. The influence of liposome surface charge and of the type of conjugate (i.e., in the carboxylic or ester form) on the biological effect is discussed.