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Modulation of melphalan resistance in glioma cells with a peripheral benzodiazepine receptor ligand-melphalan conjugate.

Abstract
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 and selective target for antineoplastic agents. A PBR ligand-melphalan conjugate (PBR-MEL) was synthesized and evaluated for cytotoxicity and affinity for PBRs. PBR-MEL (9) (i.e., 670 amu) was synthesized by coupling of two key intermediates: 4-[bis(2-chloroethyl)-amino]-L-phenylalanine ethyl ester trifluoroacetate (6) and 1-(3'-carboxylpropyl)-7-chloro-1,3- dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (8). On the basis of receptor-binding displacement assays in rat brain and glioma cells, 9 had appreciable binding affinity and displaced a prototypical PBR ligand, Ro 5-4864, with IC50 values between 289 and 390 nM. 9 displayed differential cytotoxicity to a variety of rat and human brain tumor cell lines. In some of the cell lines tested including rat and human melphalan-resistant cell lines, 9 demonstrated appreciable cytotoxicity with IC50 values in the micromolar range, lower than that of melphalan alone. The enhanced activity of 9 may reflect increased membrane permeability, increased intracellular retention, or modulation of melphalan's mechanisms of resistance. The combined data support additional studies to determine how 9 may modulate melphalan resistance, its mechanisms of action, and if target selectivity can be achieved in in vivo glioma models.
AuthorsL Kupczyk-Subotkowska, T J Siahaan, A S Basile, H S Friedman, P E Higgins, D Song, J M Gallo
JournalJournal of medicinal chemistry (J Med Chem) Vol. 40 Issue 11 Pg. 1726-30 (May 23 1997) ISSN: 0022-2623 [Print] United States
PMID9171882 (Publication Type: Journal Article)
Chemical References
  • 1-(4-butanoyl-(4-bis(2-chloroethyl)amino)phenylalanine ethyl ester)-7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one
  • Antineoplastic Agents, Alkylating
  • Benzodiazepinones
  • Receptors, GABA-A
  • 4'-chlorodiazepam
  • Melphalan
Topics
  • Animals
  • Antineoplastic Agents, Alkylating (pharmacology)
  • Benzodiazepinones (chemical synthesis, metabolism, pharmacology)
  • Brain (metabolism)
  • Brain Neoplasms (metabolism, pathology)
  • Cell Death
  • Drug Resistance, Neoplasm
  • Glioma (metabolism, pathology)
  • Humans
  • Melphalan (analogs & derivatives, chemical synthesis, metabolism, pharmacology)
  • Rats
  • Receptors, GABA-A (metabolism)
  • Tumor Cells, Cultured

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