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Aziridinyldinitrobenzamides: synthesis and structure-activity relationships for activation by E. coli nitroreductase
Nuala A Helsby1, Graham J Atwell, Shangjin Yang
1Auckland Cancer Society Research Centre, School of Medical Sciences, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, New Zealand. n.helsby@auckland.ac.nz
Journal of Medicinal Chemistry
|May 28, 2004
Summary
Researchers synthesized and studied novel variants of the drug CB 1954, finding a more soluble diol derivative that shows promise for targeted cancer therapy by selectively eliminating nitroreductase-expressing cells.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Cancer Biology
Background:
- CB 1954 is a nitroreductase (NTR) substrate used in gene-directed enzyme prodrug therapy (GDEPT) and for selective cell deletion.
- Limited drug development has focused on CB 1954, necessitating exploration of new analogs.
Purpose of the Study:
- Synthesize more soluble variants and regioisomers of CB 1954.
- Conduct structure-activity relationship (SAR) studies to optimize drug properties.
- Evaluate the efficacy and specificity of new CB 1954 analogs.
Main Methods:
- Synthesis of aziridinyl-dinitrobenzamide analogs and regioisomers.
- Determination of one-electron reduction potentials using pulse radiolysis.
- Cytotoxicity assays in NTR-transfected cell lines.
- Metabolite analysis in NTR-positive cells.
- In vivo studies in mice bearing human tumor xenografts.
Main Results:
- Several CB 1954 analogs were synthesized, with varying tolerance for side chain substitutions.
- The isomeric 2-aziridinyl-3,5-dinitrobenzamide showed selectivity but was less potent than CB 1954.
- A diol derivative demonstrated significant tumor growth delay in vivo and improved solubility.
- Hydrophilic side chains modestly reduced bystander killing efficiency.
- Analogues showed improved specificity for NTR over DT-diaphorase.
Conclusions:
- Carefully selected CB 1954 analogs may offer advantages over the parent compound.
- The diol derivative's solubility and efficacy suggest potential for targeted cancer therapy.
- The diol's reduced bystander effect could be beneficial for selective ablation of NTR-tagged normal cells.