The creation and investigation of synthetic devices that operate in biological systems will not only assist revealing complex biological processes, but aid in the development of therapeutic agents. In this dissertation, we introduced different synthetic devices based on host-rotaxanes. Host-rotaxanes have a linear molecule—axle threaded onto a circular molecule—wheel. Two blocking groups that are covalently linked to each end of the axle keep it from dethreading and one of the blocking groups serves as a binding pocket. Rotaxanes adjust their conformation through the sliding and rotating movement of wheel. This feature allows host-rotaxanes to maximize binding energy to associate with guests.
The previous studies of our group demonstrated the ability of host-[2]rotaxanes to deliver impermeable fluoresceinated pentapeptides into living cells. In this dissertation, we further investigated the cellular delivery mechanism of a cyclophane-[2]rotaxane. To make the delivery process controllable, we also designed a redox-switchable rotaxane to specifically transport material into tumors. This rotaxane should not be cellular permeable until placed in a reductive environment.
The mechanically interlocked architecture enables a host-rotaxane to maximize its binding energy when associating a guest. This feature makes host-rotaxanes a type of protein mimic. Proteins can form stable complexes with guest in aqueous phase and even extract metal cations from water though a complex conformational change to configure functional groups. As protein mimics, host-rotaxanes are ideal synthetic devices to realize these functions after appropriate binding pockets are construct rotaxanes. In this report, we created receptor mimic rotaxanes and metal binding rotaxanes to implement the above two functions of proteins.
The movement of the crown ether wheel not only changes the conformation of a host-rotaxane, but alters the physical environment in which the axle resides. The axle of our previously synthesized rotaxanes only functions as a threading component. In this dissertation, we introduce a novel rotaxane featured with a stilbene axle and eventually probe molecules within living cells. The stilbene moiety is expected to be activated by a molecule recognition event and the following dethreading of the wheel changes the fluorescence of the activated stilbene.
Last but not the least, host-rotaxanes showed cellular permeability during cellular transport study, so therapeutic reagents with enhanced bioavailability may derive from a rotaxane’s structure. In this work we developed platinum-rotaxanes as potential cancer treatment agents and investigated their cytotoxicity by comparing with cisplatin and a platinum model compound.