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Rotaxanes as Cages to Control DNA Binding, Cytotoxicity, and Cellular Uptake of a Small Molecule **
Author(s) -
Kench Timothy,
Summers Peter A.,
Kuimova Marina K.,
Lewis James E. M.,
Vilar Ramon
Publication year - 2021
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.202100151
Subject(s) - cytotoxicity , chemistry , dna , rotaxane , small molecule , combinatorial chemistry , biophysics , molecule , stereochemistry , in vitro , biochemistry , organic chemistry , supramolecular chemistry , biology
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.