University of Groningen
Seek and Destroy
Hoorens, Mark Wilhelmus Henricus
DOI:10.33612/diss.123015896
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Publication date: 2020
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Hoorens, M. W. H. (2020). Seek and Destroy: Light-Controlled Cancer Therapeutics for Local Treatment. University of Groningen. https://doi.org/10.33612/diss.123015896
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Seek and Destroy
Light-Controlled Cancer Therapeutics for Local
Treatment
On the cover:
De mooiste lampen die ik ken
Mark Wilhelmus Henricus Hoorens
PhD Thesis
Rijksuniversiteit Groningen
First edition, 2020
The work was financially supported by the Netherlands
Organization for Scientific Research (NWO), VIDI grant nr.
723.014.001
The research leading to these results has received funding from
LASERLAB-EUROPE (grant agreement no. 654148, European
Union's Horizon 2020 research and innovation programme).
Printed by Ipskamp
ISBN: 978-94-034-2498-9
e-ISBN: 978-94-034-2497-2
Seek and Destroy
Light-Controlled Cancer Therapeutics for Local Treatment
Proefschrift
ter verkrijging van de graad van doctor aan de
Rijksuniversiteit Groningen
op gezag van de
rector magnificus prof. dr. C. Wijmenga
en volgens besluit van het College voor Promoties.
De openbare verdediging zal plaatsvinden op
woensdag 22 april 2020 om 16.15 uur
door
Mark Wilhelmus Henricus Hoorens
geboren op 12 juli 1992
te Spijkenisse
Promotores
Prof. dr. W.C. Szymanski
Prof. dr. P.H. Elsinga
Prof. dr. B.L. Feringa
Beoordelingscommissie
Prof. dr. W.R. Browne
Prof. dr. R. Leurs
Prof. dr. J.M. van Dijl
Table of Content
Chapter 1 Perspective and Outline
11
1.1 Aim of the research described in this thesis 12
1.2 Thesis outline 13
1.3 References 14
Chapter 2 Reversible, Spatial and Temporal Control over
Protein Activity Using Light
17
2.1 The limitations of the traditional tools to study protein
function 18
2.2 Why is rev ersible, spatial and temporal control over protein
activ ity important? 19
2.3 Light is an emerging external stimulus to control protein
activ ity 19
2.4 Photo-control ov er enzy matic activity 21 2.5 Can bio-active molecules with photo-controlled activity be
developed for every protein? 22
2.6 The current limitation of photoswitchable bio-active
molecules as a research tool 24
2.7 Concluding remarks and future prospects 25 2.8 Appendix 1: Understanding light-controlled drugs:
molecular structure and photochemistry 26
2.9 References 27
Chapter 3 Glutamate Transporter Inhibitors with Photo‐
3.1 Introduction 32
3.2 Results and discussion 34
3.2.1 Design and sy nthesis 34
3.2.2 Photochemical properties 36 3.2.3 Biological evaluation 37 3.3 Conclusions 40 3.4 Acknowledgements 41 3.5 Experimental contributions 41 3.6 Experimental data 41 3.6.1 General remarks 41 3.6.2 Sy nthesis 42
3.6.3 Analy sis of the photochemical properties 47
3.6.4 Uptake assay 49
3.7 References 53
Chapter 4 Light-controlled inhibition of BRAF
V600Ekinase
57
4.1 Introduction 58
4.2 Results and discussion 61
4.2.1 Design and sy nthesis 61
4.2.2 Photochemical properties of compounds 2a-h 63
4.2.3 Biological evaluation 64 4.3 Conclusion 68 4.4 Acknowledgements 68 4.5 Author contributions 69 4.6 Experimental data 69 4.6.1 Inhibition studies 69 4.6.2 Cy totoxicity studies 7 3 4.7 References 7 4
Chapter 5 Towards
18F-labelling of a Photoswitchable
Bio-active Molecule
79
5.1 Introduction: 80
5.2 Results and discussion 81
5.2.1 Design 81
5.2.3 Photochemical evaluation 85
5.2.4 Enzy me inhibition studies 86
5.3 Discussion and outlook 88
5.4 Experimental contributions 88
5.5 Experimental data 88
5.5.1 General sy nthetic remarks 88
5.5.2 Sy nthetic procedures 89
5.5.3 Enzy me inhibition studies 90
5.6 References 91
Chapter 6 Iminothioindoxyl as a Molecular Photoswitch
with 100 nm Band Separation in the Visible Range
95
6.1 Introduction 96
6.2 Results and discussion 97
6.2.1 Design and sy nthesis of ITI 97 6.2.2 Solv ent effects of ITI photo-isomerization 98 6.2.3 Z-E isomerization of ITI is a fast process 102 6.2.4 Substituent effects on ITI photo-isomerization 104 6.2.5 Isomerization of ITI in aqueous solutions 107
6.3 Conclusion 107
6.4 Acknowledgements 108
6.5 Experimental contributions 108
6.6 Experimental data 109
6.6.1 General sy nthetic remarks 109
6.6.2 Sy nthetic procedures 109
6.6.3 Transient Absorption Spectroscopy 112 6.6.4 NMR Studies on ITI Photo-isomerization and thermal
relaxation 116
6.7 References 119
Chapter 7 Tuning the properties of the Iminothioindoxyl
photoswitch
125
7 .1 Introduction: 126
7 .2 Results and Discussion 128
7 .2.1 ITIs with substituents at the R1 position 128 7 .2.2 ITIs with substituents at the R2/R3 position 131
7 .2.3 The role of the sulfur in ITI photo-isomerization. 132 7 .2.4 ITIs with substituents at the R4 position 133
7 .3 Conclusion 135
7 .4 Experimental Contributions 135
7 .5 Experimental data 135
7 .5.1 General sy nthetic remarks 135
7 .5.2 Sy nthetic procedures 135
7 .5.3 Transient Absorption Spectroscopy 141
7 .6 References 143
Chapter 8 Towards pH and light dual controlled
Iminothioindoxyl photoswitches for medicine
147
8.1 Introduction: 148
8.2 Results and Discussion: 151
8.2.1 UV/VIS and NMR titrations: 151
8.2.2 Photo-isomerization of protonated ITI 154 8.2.3 Ev aluation of the potential of dual-responsive ITIs for
medicine 156
8.3 Mechanistic studies of protonated ITI photo -isomerization 157
8.4 Conclusion and outlook 159
8.5 Experimental contributions 160
8.6 Experimental data 160
8.6.1 General sy nthetic remarks 160
8.6.2 Sy nthetic procedures 160
8.6.3 Titration experiments 161
8.6.4 Transient Absorption Spectroscopy 161
8.7 References 161
Chapter 9 Appendices
165
9.1 English summary 166
9.2 Nederlandse samenv atting 168
9.3 Populairwetenschappelijke samenvatting 170
