Date

Wednesday 13 May 2026

Time

15:15 - 15:45

Location

BW030

Supervisor

Sylvestre Bonnet

2nd reviewer

Hermen Overkleeft

Jury

Mark Overhand

Proteasome inhibitors are a useful class of cytotoxic inhibitors to treat cancer. However, due to the narrow therapeutic window of proteasome inhibitors, this class of drugs is currently used only for non-solid tumors. By using the principle of Photoactivated Chemotherapy (PACT), proteasome inhibitors can be converted into light-activated prodrugs. In this work, (+)-pinanediol-protected analogs of bortezomib were synthesized and subsequently caged with ruthenium(II) polypyridyl complexes. Bortezomib analogs 1, 2, and 3 were synthesized with 89%, 35%, and 14% yield, respectively. Subsequently, [Ru(tpa)(dpa)(1)](PF6)2 ([4](PF6)2), [Ru(baptpy)(2)](PF6)2 ([5](PF6)2), and [Ru(baptpy)(3)](PF6)2 ([6](PF6)2) were synthesized with 79%, 35%, and 43% yield, respectively (tpa = N-methyl-[2,2’:6’,2”-terpyridine]-4’-carboxamide, dpa = di(pyridine-2-yl)amine, baptpy = N6,N6''-di(pyridin-2-yl)-[2,2':6',2''-terpyridine]-6,6''-diamine). [4](PF6)2, [5](PF6)2, and [6](PF6)2 were found to be stable in a 1:1 v/v H2O:acetone mixture for 2 h at 25 °C, in DMSO for 2 h at 37 °C, and in cell culture medium for 24 h at 37 °C. The inhibitory potency of the inhibitors and ruthenium complexes on the β5c, β2c, and β1c subunits of the 20S proteasome was assessed with Activity-based Profiling. The IC50 values of the inhibitors for the β5c, β2c, and β1c subunits were 17 (–4/+5) nM, 800 (–300/+500) nM, 62 (–17/+23) nM for 1, 23 (–6/+8) nM, 1400 (–600/+1800) nM, 66 (–20/+27) nM for 2, and 8 (–3/+4) nM, 100 (–50/+90) nM, 18 (–7/+10) nM for 3. The IC50,Light values of the metal complexes for the β5c, β2c, and β1c subunits were 32 (–14/+24) nM, 1600 (–1000/+n.e.) nM, 95 (–n.e./+n.e.) nM for [4](PF6)2, 22 (–3/+3) nM, 1700 (–900/+n.e.) nM, 53 (–17/+26) nM for [5](PF6)2, and 15 (–4/+5) nM, 170 (–80/+140) nM, 40 (–10/+20) nM for [6](PF6)2 (n.e. = not evaluable). The photoindices, defined as the ratio between IC50,Dark and IC50,Light, for the β5c, β2c, and β1c subunits were >94, >1.9, and >32 for [4](PF6)2, 50, >1.7, and 45 for [5](PF6)2, and 1.5, 1.1, and 0.95 for [6](PF6)2. Photosubstitution with 650 nm light on the metal complexes was performed in a 1:1 v/v H2O:acetone mixture for 2 h at 25 °C, and photosubstitution quantum yields were 0.458%, 0.557%, and 0.100% for [4](PF6)2, [5](PF6)2, and [6](PF6)2, respectively. Metal complexes [4](PF6)2 and [5](PF6)2 demonstrated great potential as PACT prodrugs activated by 650 nm light.