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

Research output: Contribution to Journal/Magazine › Journal article › peer-review

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Design and synthesis of a nitrogen mustard derivative stabilized by apo-neocarzinostatin. / Urbaniak, Michael D.; Bingham, John P.; Hartley, John A. et al.
In: Journal of Medicinal Chemistry, Vol. 47, No. 19, 09.09.2004, p. 4710-4715.

Research output: Contribution to Journal/Magazine › Journal article › peer-review

Harvard

Urbaniak, MD, Bingham, JP, Hartley, JA, Woolfson, DN & Caddick, S 2004, 'Design and synthesis of a nitrogen mustard derivative stabilized by apo-neocarzinostatin', Journal of Medicinal Chemistry, vol. 47, no. 19, pp. 4710-4715. https://doi.org/10.1021/jm040790d

APA

Urbaniak, M. D., Bingham, J. P., Hartley, J. A., Woolfson, D. N., & Caddick, S. (2004). Design and synthesis of a nitrogen mustard derivative stabilized by apo-neocarzinostatin. Journal of Medicinal Chemistry, 47(19), 4710-4715. https://doi.org/10.1021/jm040790d

Vancouver

Urbaniak MD, Bingham JP, Hartley JA, Woolfson DN, Caddick S. Design and synthesis of a nitrogen mustard derivative stabilized by apo-neocarzinostatin. Journal of Medicinal Chemistry. 2004 Sept 9;47(19):4710-4715. doi: 10.1021/jm040790d

Author

Urbaniak, Michael D. ; Bingham, John P. ; Hartley, John A. et al. / Design and synthesis of a nitrogen mustard derivative stabilized by apo-neocarzinostatin. In: Journal of Medicinal Chemistry. 2004 ; Vol. 47, No. 19. pp. 4710-4715.

Bibtex

@article{b0a097fe3d0f47aaae7b810b0ef354ec,
title = "Design and synthesis of a nitrogen mustard derivative stabilized by apo-neocarzinostatin",
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.",
keywords = "Antineoplastic Agents, Binding Sites, Chlorambucil, DNA Adducts, Drug Design, Hydrolysis, Magnetic Resonance Spectroscopy, Melphalan, Models, Molecular, Molecular Structure, Nitrogen Mustard Compounds, Protein Structure, Tertiary, Taq Polymerase, Zinostatin",
author = "Urbaniak, {Michael D.} and Bingham, {John P.} and Hartley, {John A.} and Woolfson, {Derek N.} and Stephen Caddick",
year = "2004",
month = sep,
day = "9",
doi = "10.1021/jm040790d",
language = "English",
volume = "47",
pages = "4710--4715",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "19",

}

RIS

TY - JOUR

T1 - Design and synthesis of a nitrogen mustard derivative stabilized by apo-neocarzinostatin

AU - Urbaniak, Michael D.

AU - Bingham, John P.

AU - Hartley, John A.

AU - Woolfson, Derek N.

AU - Caddick, Stephen

PY - 2004/9/9

Y1 - 2004/9/9

N2 - 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.

AB - 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.

KW - Antineoplastic Agents

KW - Binding Sites

KW - Chlorambucil

KW - DNA Adducts

KW - Drug Design

KW - Hydrolysis

KW - Magnetic Resonance Spectroscopy

KW - Melphalan

KW - Models, Molecular

KW - Molecular Structure

KW - Nitrogen Mustard Compounds

KW - Protein Structure, Tertiary

KW - Taq Polymerase

KW - Zinostatin

U2 - 10.1021/jm040790d

DO - 10.1021/jm040790d

M3 - Journal article

C2 - 15341486

VL - 47

SP - 4710

EP - 4715

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 19

ER -