Self-immolative polymers.

The investigation of synthetic polymers for biological applications is increasing as assembly techniques for generating welldefined macromolecules from artificial building blocks become more sophisticated. Synthesis techniques have now evolved such that a wide variety of functional groups can be tolerated by polymerization catalysts, and a fascinating and diverse range of macromolecular and polymeric materials has resulted. These synthetic polymers are now beginning to resemble natural counterparts in terms of molecular architectures, suprastructures, and functions. However, although there has been enormous progress on synthesis and assembly, there has been much less emphasis on the controlled depolymerization or disassembly of polymers. The limited interest in depolymerization is perhaps surprising when one considers that natural polymers are put together, modified, and dismantled with equal ease. Indeed, living systems show extraordinary abilities to move forwards and backwards along reaction pathways, and are incredibly atomefficient in doing so. The repeated generation, processing, and hydrolysis of spider silk proteins is but one example amongst many in nature of this ability to assemble and disassemble polymers. The search is on, therefore, for wholly artificial functional materials that are assembled easily yet broken down in an equally facile manner to switch between states of differing (biological) activity. One step along this road is to make polymers that are programmed through their synthesis to disassemble in ways that might be triggered environmentally to yield products that are biologically important. In recent years, the research group headed by Doron Shabat at Tel Aviv University has made significant strides in this direction, with a series of publications describing “selfimmolative” systems. Of particular interest is a study published earlier this year by Sagi et al., who described the sequential disassembly of a linear main-chain polymer by a single triggering reaction (Scheme 1). The self-immolation system is based on an ingenious design philosophy: Polymers are prepared with architectures that enable the exploitation of neighboring-group interactions, 1,6-elimination, and decarboxylation reactions. The blocked isocyanate used for the polymer-assembly reactions underwent homopolymerization in the presence of a catalyst to generate polyurethanes, which were finally capped with a trigger group. By connecting up the constituent repeat units, or monomer fragments, by the urethane linkage through para positions of an aromatic ring and with a benzylic-carbon-atom spacer, the polymers are, in effect, set up to collapse the moment the end group is removed. This triggering effect is analogous to the removal of a keystone from an arch, whereby the whole structure is destabilized and the arch collapses, except that in this case the “keystone” group is at the end of the polymer “arch” rather than in the middle. What is especially exciting about the recent research by Sagi et al. is the demonstration of cleavage cascade reactions with applications which extend well beyond programmed polymer degradation. In the first example, the single reaction to cleave the polymer chain end was used for enhancedsensitivity protein detection. By capping the polymer with 4hydroxy-2-butanone, a substrate for b elimination by the common protein bovine serum albumin (BSA), a protein sensor was installed at the head of the polymer chain. Careful monomer design enabled a fluorogenic group to be installed in the main chain. This unit exhibited low fluorescenceemission intensity when present in the carbamate form (i.e. in the polyurethane chain), but high emission intensity when released as the free amine. The incubation of the butanonecapped polymer with BSA resulted in the removal of the polymer head group, liberation of the terminal amine, and subsequent unzipping of the polymer to release the substituted 4-aminobenzyl alcohol, which in turn reported the reaction cascade through enhanced fluorescence (Scheme 2). In essence, an amplification event occurs, in that a single signal, that is, hydrolysis of an end group, gives rise to multiple outputs, in this case the release of fluorescent reporter Scheme 1. General structure of a main-chain self-immolating polymer.