8 hours (65% after 3 hours). Due to the instantaneous TCOrelease, the self-immolation of S could be fitted to a one-phase exponential decay (R 2 = 0.9998), revealing a first-order rate constant (k1) of 1.0 h -1 for the cyclization of the DMEDAcarbamate and a respective half-life (t1/2) of 42 min (Fig. ), which is similar to the t1/2 previously reported for a DMEDAcarbamate of 4-hydroxyanisole (36 min at pH 7.4 and 37 °C). To demonstrate application of the Tz/TCO-DMEDA strategy for the bioorthogonal release of phenols, we designed a prodrug of the anti-mitotic and anti-angiogenic agent combretastatin A-4 (CA4, Fig. ). The unique yet simple chemical structure and the high potency of CA4 have motivated the development of several therapeutic strategies, in particular by applying prodrugs such as CA4-phosphate (CA-4P, fosbretabulin) to overcome the poor water-solubility of the parent drug. Straightforward modification of CA4 was enabled by PNPactivation of the free phenolic OH-group yielding PNP-CA4 (10) (Fig. ). To facilitate sufficient water-solubility we used cTCO as a Tz-responsive cleavable linker, allowing incorporation of a sulfonate moiety (via the additional functional group of cTCO) to obtain the CA4-prodrug 12 (Fig. ). To incorporate the SIL, cTCO-PNP ( ) was first treated with an excess of DMEDA and then reacted with PNP-CA4 (10). Saponification of the methyl ester followed by HBTU-mediated coupling of the intermediate acid with 2-aminoethanesulfonic acid (taurine) afforded sulfo-cTCO-DMEDA-CA4 ( ) in an overall yield of 34% (Fig. ).