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2.B.60. The Interlocked Catenane/Rotaxane/Polyrotaxane (ICRP) Family

Due to their low cytotoxicity, controllable size, and unique architecture, cyclodextrin (CD)-based polyrotaxanes and polypseudorotaxanes have been considered for functions such as drug delivery, gene delivery, and tissue engineering (Li et al. 2011). CD-based biodegradable polypseudorotaxane hydrogels have been used as injectable drug delivery systems for sustained and controlled drug release. Polyrotaxanes with drug or ligand-conjugated CDs threaded on a polymer chain with biodegradable end groups may be useful for controlled, multivalent targeting delivery. Cationic polyrotaxanes consisting of multiple oligoethylenimine-grafted CDs threaded on a block copolymer chain are attractive non-viral gene carries due to the strong DNA-binding ability, low cytotoxicity, and high gene transfection efficiency. Cytocleavable end caps have been introduced in the polyrotaxane systems in order to ensure efficient endosomal escape for intracellular trafficking of DNA (Li et al. 2011).

DNA-based machines include transporters and interlocked cyclic DNA structures acting as reconfigurable catenanes, rotaxanes, and rotors (Wang et al. 2014). Interlocked circular DNA nanostructures, e.g., catenanes or rotaxanes, have been used for these and other functions (Lu et al. 2016). Naphthalene diimides (NDIs) have applications as biological sensors, molecular switching devices such as catenanes and rotaxanes and ligand-gated ion-channels (Kobaisi et al. 2016). Photoinduced electron transfer can occur in multiporphyrinic interlocked structures (Flamigni et al. 2004), and charge transfer through switchable interlinked molecules such as catenanes and rotaxanes can also occur (Jan van der Molen and Liljeroth 2010; Yang et al. 2012). Transition metal-complexed catenanes and rotaxanes are dynamic systems that can function as molecular machines (Durot et al. 2014), and interlocked cyclic DNA structures can act as reconfigurable catenanes and rotaxanes (Wang et al. 2014). Interlocked systems, rotaxanes and catenanes, have been incorporated into nanomedicine chemical platforms (Ornelas-Megiatto et al. 2015), and used as drug transporters (Wang et al. 2014; Casas-Hinestroza et al. 2019). Rotaxanes, pseudorotaxanes, and catenanes are supramolecular complexes with potential use in nanomachinery, molecular computing, and single-molecule studies and have been used to translocate proteins across ClyA nanopores (Biesemans et al. 2015). The rotaxanes described here may be structurally related to those in TC family 2.B.32.

Canton et al. 2021 described the modular design of a pseudorotaxane-based supramolecular pump and its photochemically driven autonomous nonequilibrium operation in a dissipative regime. These properties derive from careful engineering of the energy maxima and minima along the threading coordinate and their light-triggered modulation. Unlike its precursor, this second-generation system is amenable to functionalization for integration into more complex devices (Canton et al. 2021).

Rotaxanes are agents that can transport material into cells. A cleft-containing rotaxane exists in two dominant conformations ('closed' and 'open'). Conformational flexibility is important for the ability of the rotaxanes to bind guests and transport material into cells (Bao et al. 2006). A locked rotaxane exhibited a reduced capacity to transport a fluoresceinated peptide into cells, whereas the unmodified rotaxane efficiently delivers the peptide. Cellular uptake of the peptide was largely temperature and ATP independent, suggesting that the rotaxane-peptide complex passes through the cellular membrane without requiring active cell-mediated processes. The results show that the sliding motion of the wheel is necessary for the delivery of materials into cells and can enhance the association of guests (Bao et al. 2006).

Macrocyclic compounds can be transported across phospholipid bilayers by umbrella-rotaxanes (Chhun et al. 2013). They exhibit amphomorphic properties and have the ability to penetrate and cross phospholipid bilayers. An azobenzene-based molecular shuttle, PR2, can perform light-gated ion transport across lipid membranes (Wang et al. 2021). The amphiphilicity and membrane-spanning molecular length enable PR2 to insert into the bilayer membrane and efficiently transport K+ (EC50 =4.1 μm) through the thermally driven stochastic shuttle motion of the crown ether ring along the axle. The significant difference in shuttling rate between trans-PR2 and cis-PR2 induced by molecular isomerization enables a light-gated ion transport, i.e., ON/OFF in situ regulation of transport activity and single-channel current. Thus, a photoswitchable molecular machine to realize gated ion transport,  demonstrates the value of molecular machines functioning in biomembranes (Wang et al. 2021). A nanopore-type machine promotes the vectorial transport of DNA across membranes (Franceschini et al. 2013). Moreover, calixarene-based artificial ionophores mediate chloride transport across natural liposomal bilayer membranes (Pilato et al. 2021).

 

References associated with 2.B.60 family:

Bao, X., I. Isaacsohn, A.F. Drew, and D.B. Smithrud. (2006). Determining the intracellular transport mechanism of a cleft-[2]rotaxane. J. Am. Chem. Soc. 128: 12229-12238. 16967974
Biesemans, A., M. Soskine, and G. Maglia. (2015). A Protein Rotaxane Controls the Translocation of Proteins Across a ClyA Nanopore. Nano Lett 15: 6076-6081. 26243210
Canton, M., J. Groppi, L. Casimiro, S. Corra, M. Baroncini, S. Silvi, and A. Credi. (2021). Second-Generation Light-Fueled Supramolecular Pump. J. Am. Chem. Soc. 143: 10890-10894. 34282901
Casas-Hinestroza, J.L., M. Bueno, E. Ibáñez, and A. Cifuentes. (2019). Recent advances in mass spectrometry studies of non-covalent complexes of macrocycles - A review. Anal Chim Acta 1081: 32-50. 31446962
Chhun, C., J. Richard-Daniel, J. Kempf, and A.R. Schmitzer. (2013). Transport of macrocyclic compounds across phospholipid bilayers by umbrella-rotaxanes. Org Biomol Chem 11: 6023-6028. 23903771
Durot, S., V. Heitz, A. Sour, and J.P. Sauvage. (2014). Transition-metal-complexed catenanes and rotaxanes: from dynamic systems to functional molecular machines. Top Curr Chem 354: 35-70. 24563013
Flamigni, L., A.M. Talarico, J.C. Chambron, V. Heitz, M. Linke, N. Fujita, and J.P. Sauvage. (2004). Photoinduced electron transfer in multiporphyrinic interlocked structures: the effect of copper(I) coordination in the central site. Chemistry 10: 2689-2699. 15195300
Franceschini, L., M. Soskine, A. Biesemans, and G. Maglia. (2013). A nanopore machine promotes the vectorial transport of DNA across membranes. Nat Commun 4: 2415. 24026014
Jan van der Molen, S. and P. Liljeroth. (2010). Charge transport through molecular switches. J Phys Condens Matter 22: 133001. 21389503
Kobaisi, M.A., S.V. Bhosale, K. Latham, A.M. Raynor, and S.V. Bhosale. (2016). Functional Naphthalene Diimides: Synthesis, Properties, and Applications. Chem Rev 116: 11685-11796. 27564253
Li, J.J., F. Zhao, and J. Li. (2011). Polyrotaxanes for applications in life science and biotechnology. Appl. Microbiol. Biotechnol. 90: 427-443. 21360153
Lu, C.H., A. Cecconello, and I. Willner. (2016). Recent Advances in the Synthesis and Functions of Reconfigurable Interlocked DNA Nanostructures. J. Am. Chem. Soc. 138: 5172-5185. 27019201
Ornelas-Megiatto, C., T.B. Becher, and J.D. Megiatto, Jr. (2015). Interlocked systems in nanomedicine. Curr Top Med Chem 15: 1236-1256. 25858133
Pilato, S., M. Aschi, M. Bazzoni, F. Cester Bonati, G. Cera, S. Moffa, V. Canale, M. Ciulla, A. Secchi, A. Arduini, A. Fontana, and G. Siani. (2021). Calixarene-based artificial ionophores for chloride transport across natural liposomal bilayer: Synthesis, structure-function relationships, and computational study. Biochim. Biophys. Acta. Biomembr 1863: 183667. 34111414
Wang, C., S. Wang, H. Yang, Y. Xiang, X. Wang, C. Bao, L. Zhu, H. Tian, and D.H. Qu. (2021). A Light-Operated Molecular Cable Car for Gated Ion Transport. Angew Chem Int Ed Engl 60: 14836-14840. 33843130
Wang, F., B. Willner, and I. Willner. (2014). DNA-based machines. Top Curr Chem 354: 279-338. 24647836
Yang, W., Y. Li, H. Liu, L. Chi, and Y. Li. (2012). Design and assembly of rotaxane-based molecular switches and machines. Small 8: 504-516. 22267051