Modulation of Melphalan Resistance in Glioma Cells with a Peripheral Benzodiazepine Receptor Ligand−Melphalan Conjugate

摘要: Peripheral benzodiazepine receptors (PBRs) are located on the outer membrane of mitochondria, and their density is increased in brain tumors. Thus, they may serve as a unique intracellular selective target for antineoplastic agents. A PBR ligand-melphalan conjugate (PBR-MEL) was synthesized evaluated cytotoxicity affinity PBRs. PBR-MEL (9) (i.e., 670 amu) by coupling two key intermediates: 4-[bis(2-chloroethyl)-amino]-L-phenylalanine ethyl ester trifluoroacetate (6) 1-(3'-carboxylpropyl)-7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (8). On basis receptor-binding displacement assays rat glioma cells, 9 had appreciable binding displaced prototypical ligand, Ro 5-4864, with IC 50 values between 289 390 nM. displayed differential to variety human tumor cell lines. In some lines tested including melphalan-resistant lines, demonstrated micromolar range, lower than that melphalan alone. The enhanced activity reflect permeability, retention, or modulation melphalan's mechanisms resistance. combined data support additional studies determine how modulate resistance, its action, if selectivity can be achieved vivo models.