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.
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 | |
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