Diastereoselective synthesis of [1]rotaxanes via an active metal template strategy.

Despite the impressive number of interlocked molecules described in the literature over the past 30 years, only a few stereoselective syntheses of mechanically chiral rotaxanes have been reported so far. In this study, we present the first diastereoselective synthesis of mechanically planar chiral [1]rotaxanes, that has been achieved using the active template Cu-mediated alkyne-azide cycloaddition reaction. This synthetic method has been applied to the preparation of a [1]rotaxane bearing a labile stopper that can then be substituted without disruption of the mechanical bond. This approach paves the way for the synthesis of a wide variety of mechanically planar chiral [1]rotaxanes, hence allowing the study of the properties and potential applications of this class of interlocked molecular architectures.

A mechanically interlocked molecular system programmed for the delivery of an anticancer drug.

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 ß-galactosidase.

ß-Glucuronidase-responsive prodrugs for selective cancer chemotherapy: an update.

The design of novel antitumor agents allowing the destruction of malignant cells while sparing healthy tissues is one of the major challenges in medicinal chemistry. In this context, the use of non-toxic prodrugs programmed to be selectively activated by beta-glucuronidase present at high concentration in the microenvironment of most solid tumors has attracted considerable attention. This review summarizes the major progresses that have been realized in this field over the past ten years. This includes the new prodrugs that have been designed to target a wide variety of anticancer drugs, the prodrugs employed in the course of a combined therapy, the dendritic glucuronide prodrugs and the concept of ß-glucuronidase-responsive albumin binding prodrugs.