Chemical synthesis and biological evaluation of a NAD(P)H: quinone oxidoreductase-1-targeted tripartite quinone drug delivery system

Milène Volpato, Nathalie Abou-Zeid, Richard W. Tanner, Lee T. Glassbrook, James Taylor, Ian Stratford, Paul M. Loadman, Mohammed Jaffar, Roger M. Phillips

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

NAD(P)H:quinone oxidoreductase-1 (NQO1) is a potential target for therapeutic intervention but attempts to exploit NQO1 using quinone-based bioreductive prodrugs have been largely compromised by toxicity to organs that inherently express high levels of NQO1. In an attempt to circumvent this problem, this study describes the development of a tripartite quinone-based drug delivery system, the ultimate objective of which is to release a targeted therapeutic agent following the reduction of a quinone "trigger" by NQO1. Molecular modeling of drug/NQO1 interactions were conducted prior to the synthesis of N-{4-[bis-(2-chloroethyl)-amino]-phenyl}-β,β,2,4,5- pentamethyl-3,6-dioxo-1,4-cyclohexadiene-1-propanamide (prodrug 1). Prodrug 1 is a good substrate for purified NQO1 (Vmax and Km values of 11.86 ± 3.09 μmol/min/mg and 2.70 ± 1.14 μmol/L, respectively) and liquid chromatography-mass spectrometry analysis of the metabolites generated showed that lactone 3 and aniline mustard 4 were generated in a time- and NQO1-dependent manner. Chemosensitivity studies showed that prodrug 1 is selectively toxic to cells that overexpress NQO1 under aerobic conditions, and comet assay analysis confirmed the presence of elevated interstrand cross-links in NQO1-rich compared with NQO1-deficient cells. Hypoxic sensitization (hypoxic cytotoxicity ratio = 15.8) was observed in T47D cells that overexpress cytochrome P450 reductase. In conclusion, the results of this study provide mechanistic proof of principle that a tripartite benzoquinone drug delivery system is enzymatically reduced to release an active therapeutic agent. Further development of this concept to fine-tune substrate specificity for specific reductases and/or the inclusion of alternative therapeutic agents is warranted.

LanguageEnglish
Pages3122-3130
Number of pages9
JournalMolecular Cancer Therapeutics
Volume6
Issue number12
DOIs
Publication statusPublished - 1 Dec 2007
Externally publishedYes

Fingerprint

Drug Delivery Systems
NAD
Prodrugs
Oxidoreductases
Aniline Mustard
NADPH-Ferrihemoprotein Reductase
Comet Assay
Poisons
Lactones
Therapeutics
Substrate Specificity
Drug Interactions
Liquid Chromatography
Mass Spectrometry
benzoquinone

Cite this

Volpato, Milène ; Abou-Zeid, Nathalie ; Tanner, Richard W. ; Glassbrook, Lee T. ; Taylor, James ; Stratford, Ian ; Loadman, Paul M. ; Jaffar, Mohammed ; Phillips, Roger M. / Chemical synthesis and biological evaluation of a NAD(P)H : quinone oxidoreductase-1-targeted tripartite quinone drug delivery system. In: Molecular Cancer Therapeutics. 2007 ; Vol. 6, No. 12. pp. 3122-3130.
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Chemical synthesis and biological evaluation of a NAD(P)H : quinone oxidoreductase-1-targeted tripartite quinone drug delivery system. / Volpato, Milène; Abou-Zeid, Nathalie; Tanner, Richard W.; Glassbrook, Lee T.; Taylor, James; Stratford, Ian; Loadman, Paul M.; Jaffar, Mohammed; Phillips, Roger M.

In: Molecular Cancer Therapeutics, Vol. 6, No. 12, 01.12.2007, p. 3122-3130.

Research output: Contribution to journalArticle

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T2 - Molecular Cancer Therapeutics

AU - Volpato, Milène

AU - Abou-Zeid, Nathalie

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AU - Glassbrook, Lee T.

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