Photopharmacology. Willem Arend Velema

Transcription

1 Photopharmacology Willem Arend Velema

2 First edition, November 2014 The work described in this thesis was carried out at the Stratingh Institute for Chemistry, Groningen, The Netherlands. The work was financially supported by the Netherlands Organization for Scientific Research (NWOCW), the European Research Council and the Ministry of Education, Culture and Science. Cover art by Arie van t Riet: Printed by Ipskamp Drukkers BV, Enschede, The Netherlands ISBN: (Printed version) ISBN: (Electronic version)

3 Photopharmacology PhDThesis toobtainthedegreeofphdatthe UniversityofGroningen ontheauthorityofthe RectorMagnificusProf.E.Sterken andinaccordancewith thedecisionbythecollegeofdeans. Thisthesiswillbedefendedinpublicon Friday21November2014at16:15hours by WillemArendVelema bornon2august1986 ingroningen

4 Supervisor Prof.B.L.Feringa Assessmentcommittee Prof.A.J.M.Driessen Prof.A.J.Minnaard Prof.D.Trauner

5 And now, said Julian, when everything was quiet, I hope we are all ready to leave the phenomenal world and enter into the sublime? Donna Tartt in The Secret History

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7 Table of Contents Chapter 1: An Introduction to Photopharmacology Introduction Using light for controlling biological processes Design principles for creating photocontrolled drugs Pharmacological considerations Photoisomer ratio at photostationary state Wavelength tuning The halflife of thermodynamically unstable isomer Stability in the cellular environment Toxicity Design principles: concluding remarks Photopharmacology: Illustrative examples Phototethered ligands Outlook References 38 Chapter 2: Design, Synthesis and Inhibitory Activity of Potent, Photoswitchable Mast Cell Activation Inhibitors Introduction Results Design of photoswitchable inhibitors Synthesis Photoswitchable behavior of designed mast cell activation inhibitors Inhibitory activity Discussion Conclusions Experimental section LAD2 Cell culture βhexosaminidase assay. 57

8 2.5.3 Histamine assay Inhibitory activity tests Photoswitching experiments Synthesis General information Synthesis of DAC Synthesis of MAC and PAC References 66 Chapter 3: Lighttriggered Self Assembly of a Dichromonyl Compound in Water Introduction Results and discussion Design of photoswitchable hydrogelator Photoswitchable behavior of compound Aggregation studies of compound Photoswitchable hydrogelation of compound Conclusion Experimental section Photoswitching experiments cryotem Synthesis References 79 Chapter 4: Optical Control of Antibacterial Activity Introduction Results and Discussion Design and synthesis of photoswitchable antibiotic Photoswitchable behavior of compound Antibacterial activity of compound Thermal inactivation 88

9 4.2.5 Studying pharmacodynamics using cistrans isomerization Bacterial patterning Conclusion Experimental section Photoswitching experiments Bacterial strains and growth conditions Antibacterial activity and bacterial growth curves Bacterial patterning experiments Synthesis References 107 Chapter 5: Proteasome Inhibitors with Photocontrolled Activity Introduction Results and Discussion Design and synthesis of photoswitchable proteasome inhibitors Photochemical properties of photoswitchable proteasome inhibitors Biological activity of photoswitchable proteasome inhibitors Conlusion Experimental section Photoswitching experiments Competition experiments Cell culture Cytotoxicity assay Synthesis References 135

10 Chapter 6: LightControlled Bacterial Communication Introduction Results and Discussion Design and synthesis of photoswitchable homoserine lactones Photoswitchable behavior of compound Biological activity of compound Conclusion Experimental section Photoswitching experiments Bacterial strains and growth conditions Bioluminescence assay RNA isolation and cdna synthesis Gene expression with qpcr Synthesis References 154 Chapter 7: Orthogonal Control of Antibacterial Activity with Light Introduction Results and Discussion Design of photocleavable antibiotics Synthesis of photocleavable antibiotics Photochemical properties of FQNC and BPOC Antibacterial properties of FQNC and BPOC Bacterial selection using photocleavable antibiotics Conclusion Experimental section Photoswitching experiments Bacterial strains and growth conditions Antibacterial activity and bacterial growth curves Synthesis

11 General information Synthesis of FQNC and BPOC References 176 Samenvatting 179 Summary 181 Acknowledgements 184

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