Design and synthesis of a nitrogen mustard derivative stabilized by apo-neocarzinostatin
| Autor: | Dek N Woolfson, Stephen Caddick, JA Hartley, Urbaniak, JP Bingham |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
Melphalan
Models Molecular Magnetic Resonance Spectroscopy Stereochemistry Guanine Antineoplastic Agents chemistry.chemical_compound DNA Adducts Zinostatin Drug Discovery Enediyne medicine Taq Polymerase Neocarzinostatin Binding Sites Molecular Structure Hydrolysis Nitrogen mustard Protein Structure Tertiary DNA Intercalation chemistry Drug Design Nitrogen Mustard Compounds Molecular Medicine Chlorambucil DNA medicine.drug Conjugate |
| Zdroj: | Journal of medicinal chemistry. 47(19) |
| ISSN: | 0022-2623 |
| Popis: | Neocarzinostatin (NCS) is an antitumor antibiotic comprising a 1:1 protein-chromophore complex and exhibits cytotoxic action through DNA cleavage via H-abstraction. Cytotoxic activity resides with the chromophore 1 alone, while the protein (apoNCS) protects and transports labile 1. The naphthoate portion (2) of NCS chromophore (1) is important for binding to apoNCS and DNA intercalation. In this paper we describe our attempts to use apoNCS to improve the hydrolytic stability of novel bifunctional DNA alkylating agents. The nitrogen mustards, melphalan and chlorambucil, were both conjugated to 2, and the biological activities of these conjugates were assessed. Chlorambucil did not benefit from conjugation. The melphalan conjugate (6) formed covalent DNA adducts at guanine bases and exhibited greater in vitro cytotoxic activity than unmodified melphalan. Fluorescence and NMR spectroscopy showed that 6 binds to apoNCS. Binding to apoNCS-protected 6 reduced the extent of hydrolysis of the conjugate. This novel approach demonstrates for the first time that an enediyne apo-protein can be used to improve the stability of substances that are of potential interest in cancer chemotherapy. |
| Databáze: | OpenAIRE |
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