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

Publication ,  Journal Article
Kupczyk-Subotkowska, L; Siahaan, TJ; Basile, AS; Friedman, HS; Higgins, PE; Song, D; Gallo, JM
Published in: J Med Chem
May 23, 1997

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.

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Published In

J Med Chem

DOI

ISSN

0022-2623

Publication Date

May 23, 1997

Volume

40

Issue

11

Start / End Page

1726 / 1730

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Receptors, GABA-A
  • Rats
  • Melphalan
  • Medicinal & Biomolecular Chemistry
  • Humans
  • Glioma
  • Drug Resistance, Neoplasm
  • Cell Death
  • Brain Neoplasms
 

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Kupczyk-Subotkowska, L., Siahaan, T. J., Basile, A. S., Friedman, H. S., Higgins, P. E., Song, D., & Gallo, J. M. (1997). Modulation of melphalan resistance in glioma cells with a peripheral benzodiazepine receptor ligand-melphalan conjugate. J Med Chem, 40(11), 1726–1730. https://doi.org/10.1021/jm960592p
Kupczyk-Subotkowska, L., T. J. Siahaan, A. S. Basile, H. S. Friedman, P. E. Higgins, D. Song, and J. M. Gallo. “Modulation of melphalan resistance in glioma cells with a peripheral benzodiazepine receptor ligand-melphalan conjugate.J Med Chem 40, no. 11 (May 23, 1997): 1726–30. https://doi.org/10.1021/jm960592p.
Kupczyk-Subotkowska L, Siahaan TJ, Basile AS, Friedman HS, Higgins PE, Song D, et al. Modulation of melphalan resistance in glioma cells with a peripheral benzodiazepine receptor ligand-melphalan conjugate. J Med Chem. 1997 May 23;40(11):1726–30.
Kupczyk-Subotkowska, L., et al. “Modulation of melphalan resistance in glioma cells with a peripheral benzodiazepine receptor ligand-melphalan conjugate.J Med Chem, vol. 40, no. 11, May 1997, pp. 1726–30. Pubmed, doi:10.1021/jm960592p.
Kupczyk-Subotkowska L, Siahaan TJ, Basile AS, Friedman HS, Higgins PE, Song D, Gallo JM. Modulation of melphalan resistance in glioma cells with a peripheral benzodiazepine receptor ligand-melphalan conjugate. J Med Chem. 1997 May 23;40(11):1726–1730.
Journal cover image

Published In

J Med Chem

DOI

ISSN

0022-2623

Publication Date

May 23, 1997

Volume

40

Issue

11

Start / End Page

1726 / 1730

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Receptors, GABA-A
  • Rats
  • Melphalan
  • Medicinal & Biomolecular Chemistry
  • Humans
  • Glioma
  • Drug Resistance, Neoplasm
  • Cell Death
  • Brain Neoplasms