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

Journal of Medicinal Chemistry
Michael D UrbaniakStephen Caddick

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.

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Citations

May 26, 2009·Journal of Biomedical Science·Aranganathan ShanmuganathanDer-Hang Chin
Dec 5, 2012·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Yan-Bo ZhengYong-Su Zhen
Jul 8, 2008·Analytical Biochemistry·Jayachithra KandaswamyDer-Hang Chin
Jul 12, 2016·Molecular Pharmaceutics·Ethel J NgenAssaf A Gilad
Nov 30, 2018·International Journal of Molecular Sciences·Diego MontagnerCristina Marzano
Apr 25, 2007·Chembiochem : a European Journal of Chemical Biology·James R BakerStephen Caddick
Mar 26, 2010·Physical Chemistry Chemical Physics : PCCP·Bing Wang, Kenneth M Merz
Mar 26, 2010·Natural Product Reports·Zhao-Xun Liang
Mar 29, 2006·The Journal of Biological Chemistry·Parameswaran HariharanDer-Hang Chin
Mar 13, 2014·ChemMedChem·Ivonne ZuravkaRichard Göttlich
Jan 11, 2005·The Journal of Biological Chemistry·Hiroyuki TakashimaYuji Kobayashi
Feb 14, 2021·European Journal of Medicinal Chemistry·Shibo LinYang Wang
Feb 7, 2006·Bioorganic & Medicinal Chemistry·Christopher G Sudhahar, Der-Hang Chin
Jun 15, 2006·Journal of the American Chemical Society·Masayuki InoueToshio Otani
Mar 30, 2006·Journal of the American Chemical Society·Stephen CaddickDerek N Woolfson

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