Self-immolative Dendrimers.

Sometimes one comes across a piece of chemistry that makes one proud to be a chemist. I came across one such example recently at a conference on polymer therapeutics, where Doron Shabat of Tel Aviv University gave a presentation on self-immolative dendrimers1,2.
The idea behind those molecules is that the dendrons can be loaded up with drug molecules, which they deliver to a target site. At the site of action, a passivator is cleaved, which leads to the self-unravelling of the dendrimer and the release of the drug. Is is almost like a knitted jumper. Pull on a bit of loose thread and the whole thing unravels. Here is how the chemistry works:

self-immolative-dendrimers.gif

The molecule essentially consists of three elements: a target moiety, an adaptor unit and a reporter, which is usually the drug. The adaptor unit is based on 2,6-bis(hydroxymethyl)-p-cresol and therefore trifunctional. The phenolic group links to a short N.N’dimethylethylene diamine spacer, which, in turn connects to the trigger molecule. The hydroxybenzyl groups connect to reporter molecules via a carbamate linker.

Cleavage of the trigger moiety leads to an amine which cyclizes to form a cyclic N,N-dimethy urea and a phenol. The latter undregoes a 1,4-quinone methide rearrangement, immediately followed by a decarboxylation, which liberates one of the reporter molecules. Attack of a molecule of water on the methide reforms the phenol, which subsequently undergoes a second rearrangement and looses the second arm. Attack by another water molecule reforms the phenol.

Now there are some problems with this: does one really want to have (relatively toxic) monomers from a carrier scaffold floating about in cells etc, but irrespective of this, it is just a beautiful, aesthetic and elegant piece of chemistry. I have only shown the first generation dendrons here, but the synthesis has been reported up the third generation. It’ll be interesting to see whether a linear version of this will come out too….doing this with a linear polymer would of course mean, that much higher reporter/drug loadings could be achieved.

These are the key references:

[1] Amir, R. J., Pessah, N., Shamis, M., Shabat, D. Angew. Chem. Int. Ed., 42, 4494 (2003)
[2] Shamis, M. Lode, H. N., Shabat, D., J. Am. Chem. Soc., 126, 1726 (2004)

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