A class of rotaxane is created, not by encapsulating a conventional linear thread, but rather by wrapping a large cucurbituril macrocycle about a three-dimensional, cylindrical, nanosized, self-assembled supramolecular helicate as the axle. The resulting pseudo-rotaxane is readily converted into a proper interlocked rotaxane by adding branch points to the helicate strands that form the surface of the cylinder (like branches and roots on a tree trunk). The supramolecular cylinder that forms the axle is itself a member of a unique and remarkable class of helicate metallo-drugs that bind Y-shaped DNA junction structures and induce cell death. While pseudo-rotaxanation does not modify the DNA-binding properties, proper, mechanically-interlocked rotaxanation transforms the DNA-binding and biological activity of the cylinder. The ability of the cylinder to de-thread from the rotaxane (and thus to bind DNA junction structures) is controlled by the extent of branching: fully-branched cylinders are locked inside the cucurbituril macrocycle, while cylinders with incomplete branch points can de-thread from the rotaxane in response to competitor guests. The number of branch points can thus afford kinetic control over the drug de-threading and release.
Bibliographical noteFunding Information:
This work was funded by the EPSRC Physical Sciences for Health Centre (EP/L016346/1), BBSRC MIBTP (BB/M01116 X/1), the EU DNAREC Marie Curie Training Site (MEST-CT-2005-020842), an EU Marie Curie Fellowship (H2020-MSCA-IF-2018-844145), FAPESP (2019/11242-1), National Natural Science Foundation of China (21871216), and the University of Birmingham. Simulations used the Bluebear and Castles HPC facility (U. Birmingham). F.B. was supported by a student exchange from LMU Munich. We thank the Centre for Chemical and Materials Analysis (U. Birmingham), the EPSRC UK National Crystallography Service at the University of Southampton for the collection of the crystallographic data, Dr. Mirela Pascu (U. Birmingham) for some initial experiments (on L′) and Dr. Tim Barendt, Prof. Zoe Pikramenou (both U. Birmingham), Prof Alexandre Martinez (Ecole Centrale de Marseille), and Prof Benoît Colasson (U. Paris Descartes) for helpful discussions.