Ribosomal Rotaxane?: The ribosome is an extraordinarily sophisticated molecular machine, assembling amino acids into proteins based on the precise sequence dictated by messenger RNA. Lewandowski et al. (p. 189 ) have now taken a step toward the preparation of a stripped-down synthetic ribosome analog. Their machine comprises a rotaxane—a ring threaded on a rod—in which the ring bears a pendant thiol that can pluck amino acids off the rod; the terminal nitrogen then wraps around to form a peptide bond and liberate the thiol for further reaction. The system was able to link three amino acids in order from the preassembled rod.

The development of mechanically interlocked molecular systems programmed to operate autonomously in biological environments is an emerging field of research with potential medicinal applications. Within this framework, functional rotaxane- and pseudorotaxane-based architectures are starting to attract interest for the delivery of anticancer drugs, with the ultimate goal to improve the efficiency of cancer chemotherapy. Here, we report an enzyme-sensitive [2]-rotaxane designed to release a potent anticancer drug within tumor cells. The molecular device includes a protective ring that prevents the premature liberation of the drug in plasma. However, once located inside cancer cells the [2]-rotaxane leads to the release of the drug through the controlled disassembly of the mechanically interlocked components, in response to a determined sequence of two distinct enzymatic activations. Furthermore, in vitro biological evaluations reveal that this biocompatible functional system exhibits a noticeable level of selectivity for cancer cells overexpressing β-galactosidase.