Covalently acting inhibitors constitute a large and growing fraction of approved small-molecule therapeutics as well as useful tools for a variety of in vitro and in vivo applications. Here, we... Show moreCovalently acting inhibitors constitute a large and growing fraction of approved small-molecule therapeutics as well as useful tools for a variety of in vitro and in vivo applications. Here, we aimed to develop a covalent antagonist of CC chemokine receptor 2 (CCR2), a class A GPCR that has been pursued as a therapeutic target in inflammation and immuno-oncology. Based on a known intracellularly binding CCR2 antagonist, several covalent derivatives were synthesized and characterized by radioligand binding and functional assays. These studies revealed compound 14 as an intracellular covalent ligand for CCR2. In silico modeling followed by site-directed mutagenesis confirmed that 14 forms a covalent bond with one of three proximal cysteine residues, which can be engaged interchangeably. To our knowledge, compound 14 represents the first covalent ligand reported for CCR2. Due to its unique properties, it may represent a promising tool for ongoing and future studies of CCR2 pharmacology. Show less
The biological application of photoactivatable ruthenium anticancer prodrugs is limited by the need to use poorly penetrating high-energy visible light for their activation. Upconverting... Show moreThe biological application of photoactivatable ruthenium anticancer prodrugs is limited by the need to use poorly penetrating high-energy visible light for their activation. Upconverting nanoparticles (UCNPs), which produce high-energy light under near-infrared (NIR) excitation, can solve this issue, provided that they form stable, water (H2O)-dispersible nano-conjugates with the prodrug and that there is efficient energy transfer from the UCNP to the ruthenium complex. Herein, we report on the synthesis and photochemistry of the ruthenium(II) polypyridyl complex [Ru(bpy)(2)(3(H))](PF6)(2) ([1](PF6)(2)), where bpy = 2,2-bipyridine and 3(H) is a photocleavable bis(thioether) ligand modified with two phosphonate moieties. This ligand was coordinated to the ruthenium center through its thioether groups and could be dissociated under blue-light irradiation. Complex [1](PF6)(2) was bound to the surface of NaYF4:Yb3+,Tm3+@ NaYF4:Nd3+@NaYF4 core-shell-shell (CSS-)UCNPs through its bis(phosphonate) group, thereby creating a H2O-dispersible, thermally stable nanoconjugate (CSS-UCNP@[1]). Conjugation to the nanoparticle surface was found to be most efficient in neutral to slightly basic conditions, resulting in up to 2.4 x 10(3) Ru-II ions per UCNP. The incorporation of a neodymium-doped shell layer allowed for the generation of blue light using low-energy, deep-penetrating light (796 nm). This wavelength prevents the undesired heating seen with conventional UCNPs activated at 980 nm. Irradiation of CSS-UCNP@[1] with NIR light led to activation of the ruthenium complex [1](PF6)(2). Although only one of the two thioether groups was dissociated under irradiation at 50 W.cm(-2), we provide the first demonstration of the photoactivation of a ruthenium thioether complex using 796 nm irradiation of a H2O-dispersible nanoconjugate. Show less
This research describes the quest to create 'super-caffeines', substances that only produce the desired effects of caffeine, and unlike caffeine, substances that should only have to be taken in... Show moreThis research describes the quest to create 'super-caffeines', substances that only produce the desired effects of caffeine, and unlike caffeine, substances that should only have to be taken in measured, minute, controlled amounts to achieve these effects. Unless particular steps are taken to avoid it, caffeine is a very prevalent substance in our society, which almost all of us ingest in some manner on a daily basis. It is an integral part of coffee, tea and chocolate-based products, cola drinks and is even used as a supplement in painkillers. Most people recognise caffeine as a stimulant; however, have you ever wondered how and why we get not only the pick-me-up effect, but also less desirable ones, for example, the need to go to the toilet more often and the racing heart? Caffeine is an example of a ligand (a chemical compound) that acts via certain anchor points in the body, the adenosine receptors. These receptors are located throughout the body in a number of different tissues. There are four different categories of this receptor that respond specifically to a substance called adenosine, which is produced within the body when and where it is needed. Once a substance like caffeine enters the body the majority of its effects are as a result of blocking these receptors, thereby not allowing the body's own chemical compound, adenosine, to occupy the receptors. The often welcome stimulatory effects of caffeine have been found to be as a consequence of blocking a particular adenosine receptor, known as the adenosine A1 receptor. The unwelcome sideeffects mentioned earlier are often a result of caffeine's interaction with one or more of the other three adenosine receptors. The therapeutic potential for new __super-caffeines__ (so called adenosine A1 receptor antagonists) are great, for instance as cognition enhancers in the elderly. This thesis describes the design and development of several series of new compounds which help us to define, understand and further the research into adenosine receptor antagonists. The substances themselves are novel in chemical structure, have excellent affinity for the adenosine A1 receptor (very much better than that measured for caffeine) and are selective for this particular receptor above the rest of the adenosine receptor family. Show less
