In vitro fluorine-19 nuclear magnetic resonance study of the liberation of antitumor nitrogen mustard from prodrugs

Monneret, Claude

doi:10.1039/b111549a

Cited by 10 publications

(9 citation statements)

References 24 publications

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“…The lacZ gene encoding β‐gal has been recognized as the standard means of assaying clonal insertion, transcriptional activation, protein expression and interaction in molecular/cellular biology, small animal investigations, and clinical trials . So when using fluorinated nitrogen mustards as aglycones, their β‐ D ‐galactosides would work as prodrugs. Upon delivery and cleavage at the lacZ ‐transfected tumor, the fluorinated antitumor nitrogen mustards will be lacZ (or β‐gal)‐specifically released, in which the accompanied 19 F chemical shift changes and hydrolytic kinetics will recognize the presence and progression of lacZ (or β‐gal), offering a potential for simultaneous monitoring of cancer therapy.…”

Section: Resultsmentioning

confidence: 99%

Novel ¹⁹F‐MRS β‐galactosidase reporter molecules incorporated nitrogen mustard analogues

Zhao

Zhi-ming

et al. 2017

Chem Biol Drug Des

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In this study, we propose a novel molecular platform-integrated fluorinated antitumor nitrogen mustards for F-MRS assay of β-galactosidase (β-gal) activity. Following this idea, we have designed, synthesized, and characterized 2-fluoro-4-[bis(2'-chloroethyl)amino]phenyl β-D-galactopyranoside 5, 2-fluoro-4-{bis[2'-O-(β-D-galactopyranosyl)ethyl]amino}phenyl β-D-galactopyranoside 8, 2-fluoro-4-{bis[[1″-(β-D-galactopyranosyl)-1″, 2″, 3″-triazol-4″-yl]methyl] amino}phenyl β-D-galactopyranoside 14 and 2-fluoro-4-{bis[[1″-(β-D-glucopyranosyl)-1″, 2″, 3″-triazol-4″-yl]methyl]amino}phenyl β-D-galactopyranoside 15 through glycosylation and click reaction strategies, and their structures were confirmed by NMR and HRMS or elemental analysis data. Among them, 2-fluoro-4-[bis(2'-chloroethyl)amino]phenyl β-D-galacto-pyranoside 5 was found very sensitive to β-gal (E801A) in PBS at 37°C with big Δδ response. Here, we demonstrated the feasibility of this platform for assessing β-gal activity in solution, and in vitro with lacZ-transfected human MCF7 breast and PC3 prostate tumor cells, by the characterization of β-gal-responsive F-chemical shift changes Δδ and hydrolytic kinetics.

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Section: Resultsmentioning

confidence: 99%

Novel ¹⁹F‐MRS β‐galactosidase reporter molecules incorporated nitrogen mustard analogues

Zhao

Zhi-ming

et al. 2017

Chem Biol Drug Des

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“…OFPNPG specifically detected h-gal activity, but we note that 19 F NMR chemical shift response has been used by others to detect enzyme activity particularly with respect to pro-drug activation associated with gene-directed enzyme prodrug therapy. Others have examined fluorinated mustard drugs released by activity of glucuronidase [16] and carboxypeptidase G2 [17] and conversion of 5-fluorocytosine to 5-fluorouracil [6]. A major goal of our work was to seek minimally toxic gene reporter substrates and products, but we note that broad spectrum toxicity of nitrophenols could be applied to develop h-gal-activated chemotherapy using agents such as PFONPG.…”

Section: Discussionmentioning

confidence: 97%

Imaging β-galactosidase activity using 19F chemical shift imaging of LacZ gene-reporter molecule 2-fluoro-4-nitrophenol-β-d-galactopyranoside

Kodibagkar

Liu

et al. 2006

Magnetic Resonance Imaging

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“…Therefore, we continue to seek reporters with lower toxicity. As a corollary, our approach could stimulate new approaches for detecting gene-directed enzyme prodrug therapy or antibodydirected prodrug therapy (32,33). Instead of seeking to minimize product toxicity, we may seek to generate a highly toxic product that is liberated locally by ␤-gal activity.…”

Section: Discussionmentioning

confidence: 99%

¹⁹ F‐NMR detection of lacZ gene expression via the enzymic hydrolysis of 2‐fluoro‐4‐nitrophenyl β‐D‐galactopyranoside in vivo in PC3 prostate tumor xenografts in the mouse ¹

et al. 2007

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Gene therapy shows promise for treating prostate cancer and has been evaluated in several clinical trials. A major challenge that remains is to establish a method for verifying transgene activity in situ. The lacZ gene encoding beta-galactosidase historically has been the most popular reporter gene for molecular biology. We have designed a 19F NMR approach to reveal lacZ gene expression by assessing beta-galactosidase (beta-gal) activity in vivo. The substrate 2-fluoro-4-nitrophenyl beta-D-galactopyranoside (OFPNPG) is readily hydrolyzed by beta-gal with a corresponding decrease in the 19F-NMR signal from OFPNPG and the appearance of a new signal shifted 4-6 ppm upfield from the aglycone 2-fluoro-4-nitrophenol (OFPNP). We report proof of principle in cultures of PC3 prostate cancer cells using 19F NMR spectroscopy and 19F chemical shift imaging. More importantly, we demonstrate for the first time the ability to differentiate wild-type and lacZ-expressing prostate tumor xenografts in mice using this approach.

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In vitro fluorine-19 nuclear magnetic resonance study of the liberation of antitumor nitrogen mustard from prodrugs

Cited by 10 publications

References 24 publications

Novel ¹⁹F‐MRS β‐galactosidase reporter molecules incorporated nitrogen mustard analogues

Novel ¹⁹F‐MRS β‐galactosidase reporter molecules incorporated nitrogen mustard analogues

Imaging β-galactosidase activity using 19F chemical shift imaging of LacZ gene-reporter molecule 2-fluoro-4-nitrophenol-β-d-galactopyranoside

¹⁹ F‐NMR detection of lacZ gene expression via the enzymic hydrolysis of 2‐fluoro‐4‐nitrophenyl β‐D‐galactopyranoside in vivo in PC3 prostate tumor xenografts in the mouse ¹

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In vitro fluorine-19 nuclear magnetic resonance study of the liberation of antitumor nitrogen mustard from prodrugs

Cited by 10 publications

References 24 publications

Novel 19F‐MRS β‐galactosidase reporter molecules incorporated nitrogen mustard analogues

Novel 19F‐MRS β‐galactosidase reporter molecules incorporated nitrogen mustard analogues

Imaging β-galactosidase activity using 19F chemical shift imaging of LacZ gene-reporter molecule 2-fluoro-4-nitrophenol-β-d-galactopyranoside

19 F‐NMR detection of lacZ gene expression via the enzymic hydrolysis of 2‐fluoro‐4‐nitrophenyl β‐D‐galactopyranoside in vivo in PC3 prostate tumor xenografts in the mouse 1

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Novel ¹⁹F‐MRS β‐galactosidase reporter molecules incorporated nitrogen mustard analogues

Novel ¹⁹F‐MRS β‐galactosidase reporter molecules incorporated nitrogen mustard analogues

¹⁹ F‐NMR detection of lacZ gene expression via the enzymic hydrolysis of 2‐fluoro‐4‐nitrophenyl β‐D‐galactopyranoside in vivo in PC3 prostate tumor xenografts in the mouse ¹