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Design and synthesis of a nitrogen mustard derivative stabilized by apo-neocarzinostatin

Urbaniak, MD; Bingham, JP; Hartley, JA; Woolfson, DN; Caddick, S; (2004) Design and synthesis of a nitrogen mustard derivative stabilized by apo-neocarzinostatin. J MED CHEM , 47 (19) 4710 - 4715. 10.1021/jm040790d.

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Abstract

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 I 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 apoprotein can be used to improve the stability of substances that are of potential interest in cancer chemotherapy.

Type: Article
Title: Design and synthesis of a nitrogen mustard derivative stabilized by apo-neocarzinostatin
DOI: 10.1021/jm040790d
Keywords: ANTINEOPLASTIC AGENTS, SEQUENCE SPECIFICITY, ANILINE MUSTARDS, CHROMOPHORE, BINDING, CHROMOPROTEIN, APOPROTEIN, INTERCALATION, NAPHTHALENE, ACID
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry
URI: http://discovery.ucl.ac.uk/id/eprint/9122
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