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.
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Authors | L Kupczyk-Subotkowska, T J Siahaan, A S Basile, H S Friedman, P E Higgins, D Song, J M Gallo |
Journal | Journal of medicinal chemistry
(J Med Chem)
Vol. 40
Issue 11
Pg. 1726-30
(May 23 1997)
ISSN: 0022-2623 [Print] United States |
PMID | 9171882
(Publication Type: Journal Article)
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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
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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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