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Rational Design of a Dual-Mode Optical and Chemical Prodrug

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Abstract

Purpose

The purpose of this study is to demonstrate the rational design and behaviour of the first dual-mode optical and chemical prodrug, exemplified by an acetyl salicylic acid-based system.

Methods

A cyclic 1,4-benzodioxinone prodrug was synthesised by reaction of 3,5-dimethoxybenzoin and acetyl salicoyl chloride with pyridine. After purification by column chromatography and recrystallization, characterization was achieved using infrared and NMR spectroscopies, mass spectrometry, elemental analysis and single crystal X-ray diffraction. Light-triggered drug liberation was characterised via UV-visible spectroscopy following low-power 365 nm irradiation for controlled times. Chemical drug liberation was characterised via UV-visible spectroscopy in pH 5.5 solution.

Results

The synthetic method yielded pure prodrug, with full supporting characterisation. Light-triggered drug liberation proceeded at a rate of 8.30 × 10−2 s−1, while chemical, hydrolytic liberation proceeded independently at 1.89 × 10−3 s−1. The photochemical and hydrolytic reactions were both quantitative.

Conclusions

This study demonstrates the first rational dual-mode optical and chemical prodrug, using acetyl salicylic acid as a model, acting as a paradigm for future dual-mode systems. Photochemical drug liberation proceeds 44 times faster than chemical liberation, suggesting potential use in drug-eluting medical devices where an additional burst of drug is required at the onset of infection.

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Abbreviations

2:

2-[1-(3,5-dimethoxyphenyl)-2-oxo-2-phenylethoxy]-2-methyl-1,3-benzodioxin-4-one

NMR:

nuclear magnetic resonance

PDT:

photodynamic therapy

TMS:

tetramethylsilane

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AcknowledgmentS

The receipt of a Royal Society University Research Fellowship (to McCoy), funding from Queen’s University Belfast (to Rooney) and use of the EPSRC National Mass Spectrometry Service Centre, Swansea is gratefully acknowledged.

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Authors and Affiliations

  1. School of Pharmacy, Queen’s University Belfast, Belfast, BT9 7BL, UK

    Colin P. McCoy, Clare Rooney, David S. Jones & Sean P. Gorman

  2. School of Chemistry and Chemical Engineering, Queen’s University Belfast, Belfast, BT9 5AG, UK

    Mark Nieuwenhuyzen

Authors
  1. Colin P. McCoy
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  2. Clare Rooney
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  3. David S. Jones
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  4. Sean P. Gorman
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  5. Mark Nieuwenhuyzen
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Correspondence to Colin P. McCoy.

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McCoy, C.P., Rooney, C., Jones, D.S. et al. Rational Design of a Dual-Mode Optical and Chemical Prodrug. Pharm Res 24, 194–200 (2007). https://doi.org/10.1007/s11095-006-9145-8

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  • DOI: https://doi.org/10.1007/s11095-006-9145-8

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