Subsequent Fmoc-deprotection by treatment with a piperidine solution and HATU-mediated amide coupling with Fmoc-4-aminobenzoic acid yielded the resin-bound key intermediate 8 (Scheme 1B). From this point, the diversification of linker length was introduced in the last steps (Scheme 1C). To this end, the Fmoc-protecting group of 8 was cleaved and the subsequent HATU-mediated amide coupling with either Fmoc-8-aminooctanoic acid or Fmoc-4-aminobutanoic acid yielded the PHOTAC precursors 9 and 10. In the last step of the synthesis, the photoswitchable CRBN ligand 4 and the intermediates 8, 9, and 10 were subjected to an HATU-mediated amide coupling to obtain the final PHOTACs 11-13. First, the CRBN ligand 4 was converted into the corresponding carboxylic acid by treatment with trifluoroacetic acid (TFA). The resin-bound HDAC6 ligands 8, 9 and 10 were then Fmocdeprotected followed by an amide coupling with the photoswitchable CRBN ligand. After the successful amide coupling reactions, the products were cleaved from the resin and purified by preparative HPLC to yield the PHOTACs 11-13 in > 95% purity. The positive control A6 was synthesized according to our previously published procedure. The most important step in the photochemical evaluation of the synthesized PHOTACs was to confirm their ability to switch from the trans-to the cis-state. In order to investigate this, the UV spectra of the respective PHOTACs 11-13 were measured in the dark. After illumination with light at a wavelength of 390 nm, the UV spectra were measured again, and the two distinct spectra were overlaid (Figure ). This experiment was performed at a room temperature of 22 °C and at the physiological temperature of 37 °C. All synthesized PHOTACs showed the same overlaid spectra regardless of the temperature, confirming their intrinsic ability to switch from the trans-to the cis-state independently of temperature. This ensures the possibility for a cellular use of the synthesized PHOTACs. To investigate whether the photoactivated PHOTACs show a half-life long enough to induce degradation of the target protein, the half-lifes of PHOTACs 11-13 were measured photometrically. To this end, the absorbance at 370 nm was measured prior to illumination for normalization. After irradiation with the appropriate wavelength for 5 minutes the absorbance at 370 nm was measured over a time period of 20 hours at a temperature of 37 °C to calculate the respective half-life times of the cis-isomers at physiological temperatures.