Rotaxanes as cages to control DNA binding, cytotoxicity, and cellular uptake of a small molecule

Timothy Kench; Peter A. Summers; Marina K. Kuimova; James E.M. Lewis; Ramon Vilar

doi:10.1002/anie.202100151

Rotaxanes as cages to control DNA binding, cytotoxicity, and cellular uptake of a small molecule

Timothy Kench, Peter A. Summers, Marina K. Kuimova, James E.M. Lewis^*, Ramon Vilar^*

^*Corresponding author for this work

Chemistry

Research output: Contribution to journal › Article › peer-review

8 Citations (Scopus)

10 Downloads (Pure)

Abstract

The efficacy of many drugs can be limited by undesirable properties, such as poor aqueous solubility, low bioavailability, and “off-target” interactions. To combat this, various drug carriers have been investigated to enhance the pharmacological profile of therapeutic agents. In this work, we demonstrate the use of mechanical protection to “cage” a DNA-targeting metallodrug within a photodegradable rotaxane. More specifically, we report the synthesis of rotaxanes incorporating as a stoppering unit a known G-quadruplex DNA binder, namely a Pt^II-salphen complex. This compound cannot interact with DNA when it is part of the mechanically interlocked assembly. The second rotaxane stopper can be cleaved by either light or an esterase, releasing the Pt^II-salphen complex. This system shows enhanced cell permeability and limited cytotoxicity within osteosarcoma cells compared to the free drug. Light activation leads to a dramatic increase in cytotoxicity, arising from the translocation of Pt^II-salphen to the nucleus and its binding to DNA.

Original language	English
Pages (from-to)	10928-10934
Number of pages	7
Journal	Angewandte Chemie - International Edition
Volume	60
Issue number	19
Early online date	12 Feb 2021
DOIs	https://doi.org/10.1002/anie.202100151
Publication status	Published - 3 May 2021

Bibliographical note

Funding Information:
The Engineering and Physical Sciences Research Council (EPSRC) of the UK is thanked for financial support including a studentship to T.K. and a fellowship for M.K.K (EP/I003983/1). Imperial College London is thanked for support for this project via the Excellence Fund for Frontier Research (P.A.S., M.K.K. and R.V.) and the Imperial College Research Fellowship program (J.E.M.L.). J.E.M.L. thanks Prof Matthew Fuchter for access to resources and useful discussions.

Publisher Copyright:
© 2021 Wiley-VCH GmbH

Keywords

cellular imaging
G-quadruplexes
photocaging
platinum
rotaxanes

ASJC Scopus subject areas

Catalysis
General Chemistry

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10.1002/anie.202100151

KenchT2021Rotaxanes
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Cite this

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abstract = "The efficacy of many drugs can be limited by undesirable properties, such as poor aqueous solubility, low bioavailability, and “off-target” interactions. To combat this, various drug carriers have been investigated to enhance the pharmacological profile of therapeutic agents. In this work, we demonstrate the use of mechanical protection to “cage” a DNA-targeting metallodrug within a photodegradable rotaxane. More specifically, we report the synthesis of rotaxanes incorporating as a stoppering unit a known G-quadruplex DNA binder, namely a PtII-salphen complex. This compound cannot interact with DNA when it is part of the mechanically interlocked assembly. The second rotaxane stopper can be cleaved by either light or an esterase, releasing the PtII-salphen complex. This system shows enhanced cell permeability and limited cytotoxicity within osteosarcoma cells compared to the free drug. Light activation leads to a dramatic increase in cytotoxicity, arising from the translocation of PtII-salphen to the nucleus and its binding to DNA.",

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Rotaxanes as cages to control DNA binding, cytotoxicity, and cellular uptake of a small molecule

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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