Chemists based in Japan have developed an anti-cancer prodrug activation strategy that takes advantage of increased endogenous levels of acrolein at tumor sites. This could reduce side effects that are often serious drawbacks of cancer therapy by targeting the drug release directly into the cancerous tissue to avoid healthy cells.

Many researchers in the field of chemical biology combine bioorthogonal chemistry, in which reactions occur in living things without disrupting normal biological processes, with click chemistry to convert prodrugs into active substances.

The copper-catalyzed cycloaddition reaction between acetylene and azide is a well-known example of click chemistry. RIKEN’s Katsunori Tanaka and his team looked for similar reactions that would be applicable to in vivo models if they accidentally found arylazides to react with acrolein. Acrolein is a small unsaturated aldehyde that is produced by cancer cells and thus acts as a cancer biomarker. The group found that acrolein is made in many different types of cancer cells while previously it was difficult to find biomarkers that were more general than specific to a particular cancer.

A picture showing the drug release strategy

Using the cycloaddition reaction between arylazides and acrolein as a diagnostic tool, they developed a coumarin-based compound that releases coumarin when it encounters acrolein, resulting in an easily detectable increase in fluorescence. Success encouraged them to consider using the reaction in a drug delivery strategy. They replaced the coumarin moiety with mitomycin C, doxorubicin, and paclitaxel, all widely used chemotherapy drugs with toxic side effects, to create prodrugs that would hopefully deliver the drug to the tumor without causing off-target problems. In vitro studies showed that the mitomycin prodrug had better drug delivery efficacy and therefore more selective cytotoxicity, and this was tested in vivo. Mouse models showed that the prodrug actually stayed in the cancer cells, where it reacted with the acrolein, only releasing the drug into the target area, inhibiting tumor growth while limiting adverse side effects.

‘We’re doing a click-like reaction in cancer to treat the cancer; That’s our concept, ”says Tanaka. Many current approaches to prodrug involve delivering two components to the desired target – traditional click reactions depend on a ligand or enzyme being administered separately. This strategy avoids the use of a second component by using endogenous acrolein.

Other researchers working in the field of prodrug activation have been impressed with the details that have gone into the work, as well as the results. “What Tanaka reported is a very clever and very innovative application of abnormal metabolism at the tumor site,” says Binghe Wang of Georgia State University, USA. And Floris Rutjes from Radboud University in the Netherlands comments: “It’s a very interesting approach. Splitting the prodrug in this way is very new. ‘


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