Methotrexate Containing Oligopeptide Conjugates: Synthesis and in vitro Cytostatic Effect

摘要

Methotrexate (4-amino-10-methylfolic acid, MTX) was the first antimetabolite, used in the treatment of childhood acute lymphoblastic leukemia. After the internalization MTX inhibits key enzymes in the folic acid metabolism, therefore it disturbs the purine and pyrimidine biosynthesis, inhibits the DNA replication and causes cell death. MTX undergoes polyglutamylation after the cellular uptake and these conjugates inhibit irreversibly the dihydrofolate reductase and the thymidylate synthase [1]. These derivatives containing three or more Glu residues (MTX-Glu_n) arrest the efflux of MTX from cells [2] and interestingly cannot be internalized into cells via the transport system responsible for MTX influx [3]. One reason responsible for MTX-resistance is the defective antifolate polyglutamylation due to decreased enzyme expression and/or inactivating mutations. Therefore the transport of MTX-Glu_n into cells may result in effective drug which is able to avoid the development of resistance. Cell penetrating peptides may be useful tools to deliver MTX-Glu_n into cells [4]. In addition, oligo-or polypeptides coupled with MTX or its derivative could improve its biological activity, like antitumour or antileishmania effect [5-7].