Monitoring of Biological One-Electron Reduction by ¹⁹F NMR Using Hypoxia Selective Activation of an ¹⁹F-Labeled Indolequinone Derivative

Abstract

Biological reduction of fluorine-labeled indolequinone derivative (IQ-F) was characterized by (19)F NMR for quantitative molecular understanding. The chemical shift change in (19)F NMR allowed monitoring of the enzymatic reduction of IQ-F. Upon hypoxic treatment of IQ-F with NADPH:cytochrome P450 reductase, IQ-F was activated via catalytic one-electron reduction to release nonafluoro-tert-butyl alcohol (F-OH), while the formation of F-OH was significantly suppressed under aerobic conditions. Similar hypoxia-selective reduction of IQ-F occurred within A549 cells, which expresses NADPH:cytochrome P450 reductase. The kinetic analysis was also performed to propose a reaction mechanism. The molecular oxygen slightly prevents the binding of IQ-F to reductase, while the rate of net reaction was decreased due to oxidation of a semiquinone anion radical intermediate generated by one-electron reduction of IQ-F. The disappearance of IQ-F and appearance of F-OH were imaged by (19)F fast spin echo, thus visualizing the hypoxia-selective reduction of IQ-F by means of MR imaging.

Dual 19F/1H MR Gene Reporter Molecules for in Vivo Detection of β-Galactosidase

“…The multimodality approach represents a new paradigm exploiting 19 F NMR together with both T 1 and T 2 1 H MRI contrast to reveal the presence or absence of enzyme activity. The observations are in accord with renewed excitement and innovations in 19 F NMR notably for detecting enzyme activity 37, 39-42 .…”

Engineering of inorganic nanoparticles as magnetic resonance imaging contrast agents

“…219-222 Although in this review article we have discussed various strategies based on NPs for efficient MRI, there has been no literature report on hypoxia-responsive NPs as MRI CAs except on several chemical complexes for hypoxia-related MRI such as T 1 or T 2 CAs, 223 19 F-based probes, 224 and CEST probes. 86 We believe that research on this subject is likely already in progress, and the NPs that respond to hypoxia via , for example, valency change, size/morphology variation, assembly, and disassembly for enhanced MRI, will likely play multiple roles in accurate and noninvasive delineation of hypoxic areas, more precise and effective treatment, and real-time and noninvasive monitoring of therapeutic efficacy.…”

Bidentate and Tetradentate β‐Aminovinyl Trifluoromethylated Ketones and Their Copper(II) Complexes: Synthesis, Characterization and Redox Chemistry

“…[32][33][34] Fluorine is also a useful probe in 19 F NMR spectroscopy with potential implications in biology. [35] In addition, the electron-withdrawing effect of fluorine should alter the redox properties of the ligands and metal complexes and could help cocrystallization due to the enhanced volatility of the latter. [27] In continuation of our recent studies on the design of new polyfunctional enaminone-based ligands and their metal complexes, which can be used as new materials and are potential therapeutic agents, we wish to present the syntheses of a series of bidentate (NO) and tetradentate (N 2 O 2 ) enaminone-based ligands (Figures 2 and 3).…”