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

Urbaniak, Michael D. and Bingham, John P. and Hartley, John A. and Woolfson, Derek N. and Caddick, Stephen (2004) Design and synthesis of a nitrogen mustard derivative stabilized by apo-neocarzinostatin. Journal of Medicinal Chemistry, 47 (19). pp. 4710-4715. ISSN 0022-2623

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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 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.

Item Type: Journal Article
Journal or Publication Title: Journal of Medicinal Chemistry
Uncontrolled Keywords: /dk/atira/pure/subjectarea/asjc/1300/1313
Subjects:
Departments: Faculty of Health and Medicine > Biomedical & Life Sciences
ID Code: 66400
Deposited By: ep_importer_pure
Deposited On: 17 Sep 2013 08:08
Refereed?: Yes
Published?: Published
Last Modified: 22 Jun 2019 06:19
URI: https://eprints.lancs.ac.uk/id/eprint/66400

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