We report the application of the click Michael-type additionr eactiont ov inyl sulfone or vinyl sulfonate groups in the synthesis of rotaxanes through the threading-and-capping method. This methodology has proven to be efficient and versatile as it allowed the preparation of rotaxanes using template approaches based on different noncovalent interactions (i.e.,d onor-acceptor p-p interactions or hydrogen bonding) in yieldso fg enerally 60-80 %a nd up to 91 % aided by the mild conditions required (room temperature or 0 8Ca nd am ild base such as Et 3 No r4 -(N,N-dimethylamino)pyridine (DMAP)). Furthermore, the use of vinyl sulfonate moieties, whicha re suitable motifs for coupling-and-decoupling (CAD) chemistry,i mpliesa nother advantage because it allowst he controlled chemical disassembly of the rotaxanes into their components through nucleophilic substitution of the sulfonatesr esultingf rom the capping step with at hiol underm ildconditions (Cs 2 CO 3 and room temperature).

Bisphosphonates (BPs) are bone-binding molecules that provide targeting capabilities to bone cancer cells when conjugated with drug-carrying polymers. This work reports the design, synthesis, and biological evaluation of polyethyleneimine–BP–cyclodextrin (PEI-BP-CD) ternary conjugates with supramolecular capabilities for the loading of antineoplastic drugs. A straightforward, modular, and versatile strategy based on the click aza-Michael addition reaction of vinyl sulfones (VSs) allows the grafting of BPs targeting ligands and βCD carrier appendages to the PEI polymeric scaffold. The in vitro evaluation (cytotoxicity, cellular uptake, internalization routes, and subcellular distribution) for the ternary conjugates and their doxorubicin inclusion complexes in different bone-related cancer cell lines (MC3T3-E1 osteoblasts, MG-63 sarcoma cells, and MDA-MB-231 breast cancer cells) confirmed specificity, mitochondrial targeting, and overall capability to mediate a targeted drug transport to those cells. The in vivo evaluation using xenografts of MG-63 and MDA-MB-231 cells on mice also confirmed the targeting of the conjugates.

By applying a combination of the coupling-and-decoupling (CAD) chemistry of the vinyl sulfonate group with the click thia-Michael addition to the vinyl sulfone group (MAVS) we performed the irreversible unidirectional...