Design and development of photoswitchable DFG-Out RET kinase inhibitors

REarranged during Transfection (RET) is a transmembrane receptor tyrosine kinase that is required for development of multiple human tissues, but which is also an important contributor to human cancers. RET activation through rearrangement or point mutations occurs in thyroid and lung cancers. Furthermore, activation of wild type RET is an increasingly recognized mechanism promoting tumor growth and dissemination of a much broader group of cancers. RET is therefore an attractive therapeutic target for small-molecule kinase inhibitors. Non-invasive control of RET signaling with light offers the promise of unveiling its complex spatiotemporal dynamics in vivo. In this work, photoswitchable DFG-out RET kinase inhibitors based on heterocycle-derived azobenzenes were developed, enabling photonic control of RET activity. Based on the binding mode of DFG-out kinase inhibitors and using RET kinase as the test model, we developed a photoswitchable inhibitor with a quinoline “head” constituting the azoheteroarene. This azo compound was further modified by three different strategies to increase the difference in biological activity between the E-isomer and the light enriched Z-isomer. Stilbene-based derivatives were used as model compounds to guide in the selection of substituents that could eventually be introduced to the corresponding azo compounds. The most promising quinoline-based compound showed more than a 15-fold difference in bioactivity between the two isomers in a biochemical assay. However, the same compound showed a decreased Z/E (IC50) ratio in the cellular assay, tentatively assigned to stability issues. The corresponding stilbene compound gave a Z/E (IC50) ratio well above 100, consistent with that measured in the biochemical assay. Ultimately, a 7-azaindole based photoswitchable DFG-out kinase inhibitor was shown to display more than a 10-fold difference in bioactivity between the two isomers, in both a biochemical and a cell-based assay, as well as excellent stability even under reducing conditions

Small-molecule layers for devices -Evaporation growth and characterization of thin films

Small-molecule layers for devices- Evaporation growth and characterization of thin filmsM\ue5ns AndreassonApplied Semiconductor PhysicsDepartment of Microtechnology and NanoscienceChalmers University of TechnologyAbstractOrganic semiconductors constitute a relatively recent group of materials available for the electronic device designer. Substantially cheaper production technologies and integration with plastic materials are anticipated. Many different devices have been realized such as organic light emitting devices (OLED\u27s), photovoltaic cells and transistors.This thesis describes vacuum-evaporation growth of small-molecule, thin film layers for device applications. The work covers three main parts. The first describes an organic molecular beam deposition system and the initial growth made for the purpose to determine the operational parameters. The molecular flux as a function of evaporation source temperature is measured and the relation between the thickness monitor reading and the real thickness of the film are determined. For this purpose thin films of the well known molecule 3,4,9,10 perylene tetra carboxylic dianhydride is used. The film surfaces are characterized by reflective high energy electron diffraction and atomic force microscopy. They show amorphous and polycrystalline film with smooth to rough surface appearance depending on substrate and growth condition.The second part is an ultra violet photoemission study of thin films of copper phtalocyanine (CuPc) deposited on two differently treated indium tin oxide (ITO) substrates, wet treated or wet treated and subsequently heated respectively. Thin films of CuPc are commonly used in OLED\u27s as a hole injection layer. Both the electronic properties of the substrate and the CuPc are found to depend on the substrate treatment. Specifically we find that the ITO workfunction is increased ~0.4-0.6 eV after heating, and that the highest occupied molecular orbital (HOMO) is shifted ~0.5 eV to a lower binding energy on the heated substrate. The shift in HOMO is interpreted as different Fermi level pinning at a spin split Cu derived orbital on the two surfaces.Finally three different fluorescent dopants are investigated in a standard OLED structure, 9,10-bis(phenyl-ethenyl)anthracene (BPEA), Zincporphyrin (ZnP), and Porhyrin (H2P). Current-voltage measurements show that BPEA doping increases the turn-on voltage whereas it remains the same for ZnP and H2P devices. Electroluminescence spectra show that BPEA has little effect on the emission spectra while ZnP and H2P doping result in a clear change with an almost complete energy transfer for the latter.Keywords: molecular semiconductors, OLED, evaporation deposition, CuPc, PTCD

Thermal evaporation of small molecules-A study of interfacial, bulk and device properties for molecular electronics

Electronic devices based on organic materials have recently become an emerging technology for many applications. Promising aspects are the compatibility with almost any substrate and low cost processing methods. The more or less infinite number of organic molecules as well as the means to tailor the molecular properties through different chemical reactions further extends the possibilities for devices. The organic device is a complex structure. In order to fully understand and improve its properties, both fundamental as well as device issues must be treated in parallel. A first, major part of this thesis is a characterization of the chemical composition and surface morphology of the transparent electrode material indium tin oxide (ITO) and its effect on the initial growth of molecules and devices. One particular system is the copper phtalocyanine (CuPc)/ITO interface. The Fermi level of ITO is highly sensitive to surface treatments and have a clear effect on the electronic levels in the CuPc layer with two distinct pinning levels formed based on the work function of the ITO. Further, we have investigated the molecular order in thin films of CuPc grown under a magnetic field on ITO, and found that the orientation and order of the molecules in the films can be changed. We have also studied the initial interaction of CuPc and 3,4,9,10-Perylene tetracarboxylic dianhydride (PTCDA) with Cu(100). Both molecules adsorb very strongly in the first monolayer and this is reflected in the formation of interface states observable with UV photoemission spectroscopy. The mechanisms behind these states are different for the two molecules. The PTCDA molecules undergoes a chemical reaction with the Cu surface with the loss of oxygen atoms as a consequence, whereas the interface state in the case of CuPc is interpreted as a quantum well state formed in the first monolayer which is quenched as the film thickness is increasing.The second part of the thesis concerns device studies. In order to increase the efficiency of n-type organic field effect transistors, we have studied the influence of grafting self assembly monolayers (SAM’s) on the contacts and substrate surface. We found that the SAM’s decreased the contact resistance with 1-2 orders of magnitude and increased the device mobility ~10 times. We believe the reason for this was two-fold. First, the SAM’s changed the work function of the gold contacts, secondly, they also affected the hydrophobic properties of the substrate which allowed the solution of the organic molecules to more easily flow down into the contact channels, thus improving the film quality and the efficiency. Another important device is the OLED, for which we have investigated the effect of different ITO preparations on the efficiency. It was found that an oxidative treatment with UV-light followed by nitric acid, decreased the device turn-on voltage from ~19 to ~2V. This was contributed to a reduced hole-injection barrier, due to an increased ITO work function. We have also studied the influence of fluorescent dopants. The doping molecules were porphyrin derivatives with different central atoms, zinc and hydrogen. Both porphyrins affected the light emission with strong new peaks (red shifted) in the spectra. Further, the position of the spectral peaks of the porphyrins are such that the inclusion of different porphyrin dopants in the same device may allow for a white emission OLED, which is important for solid state lighting applications. Finally the thesis also includes studies of encapsulation of OLED’s. We have shown that it is possible with a simple technique to substantially prolong the lifetime of the device. Encapsulated devices were twice as efficient after two weeks compared to non-encapsulated ones

Thermal evaporation of small molecules-A study of interfacial, bulk and device properties for molecular electronics

Electronic devices based on organic materials have recently become an emerging technology for many applications. Promising aspects are the compatibility with almost any substrate and low cost processing methods. The more or less infinite number of organic molecules as well as the means to tailor the molecular properties through different chemical reactions further extends the possibilities for devices. The organic device is a complex structure. In order to fully understand and improve its properties, both fundamental as well as device issues must be treated in parallel. A first, major part of this thesis is a characterization of the chemical composition and surface morphology of the transparent electrode material indium tin oxide (ITO) and its effect on the initial growth of molecules and devices. One particular system is the copper phtalocyanine (CuPc)/ITO interface. The Fermi level of ITO is highly sensitive to surface treatments and have a clear effect on the electronic levels in the CuPc layer with two distinct pinning levels formed based on the work function of the ITO. Further, we have investigated the molecular order in thin films of CuPc grown under a magnetic field on ITO, and found that the orientation and order of the molecules in the films can be changed. We have also studied the initial interaction of CuPc and 3,4,9,10-Perylene tetracarboxylic dianhydride (PTCDA) with Cu(100). Both molecules adsorb very strongly in the first monolayer and this is reflected in the formation of interface states observable with UV photoemission spectroscopy. The mechanisms behind these states are different for the two molecules. The PTCDA molecules undergoes a chemical reaction with the Cu surface with the loss of oxygen atoms as a consequence, whereas the interface state in the case of CuPc is interpreted as a quantum well state formed in the first monolayer which is quenched as the film thickness is increasing.The second part of the thesis concerns device studies. In order to increase the efficiency of n-type organic field effect transistors, we have studied the influence of grafting self assembly monolayers (SAM’s) on the contacts and substrate surface. We found that the SAM’s decreased the contact resistance with 1-2 orders of magnitude and increased the device mobility ~10 times. We believe the reason for this was two-fold. First, the SAM’s changed the work function of the gold contacts, secondly, they also affected the hydrophobic properties of the substrate which allowed the solution of the organic molecules to more easily flow down into the contact channels, thus improving the film quality and the efficiency. Another important device is the OLED, for which we have investigated the effect of different ITO preparations on the efficiency. It was found that an oxidative treatment with UV-light followed by nitric acid, decreased the device turn-on voltage from ~19 to ~2V. This was contributed to a reduced hole-injection barrier, due to an increased ITO work function. We have also studied the influence of fluorescent dopants. The doping molecules were porphyrin derivatives with different central atoms, zinc and hydrogen. Both porphyrins affected the light emission with strong new peaks (red shifted) in the spectra. Further, the position of the spectral peaks of the porphyrins are such that the inclusion of different porphyrin dopants in the same device may allow for a white emission OLED, which is important for solid state lighting applications. Finally the thesis also includes studies of encapsulation of OLED’s. We have shown that it is possible with a simple technique to substantially prolong the lifetime of the device. Encapsulated devices were twice as efficient after two weeks compared to non-encapsulated ones

Small-molecule layers for devices -Evaporation growth and characterization of thin films

Small-molecule layers for devices- Evaporation growth and characterization of thin filmsM\ue5ns AndreassonApplied Semiconductor PhysicsDepartment of Microtechnology and NanoscienceChalmers University of TechnologyAbstractOrganic semiconductors constitute a relatively recent group of materials available for the electronic device designer. Substantially cheaper production technologies and integration with plastic materials are anticipated. Many different devices have been realized such as organic light emitting devices (OLED\u27s), photovoltaic cells and transistors.This thesis describes vacuum-evaporation growth of small-molecule, thin film layers for device applications. The work covers three main parts. The first describes an organic molecular beam deposition system and the initial growth made for the purpose to determine the operational parameters. The molecular flux as a function of evaporation source temperature is measured and the relation between the thickness monitor reading and the real thickness of the film are determined. For this purpose thin films of the well known molecule 3,4,9,10 perylene tetra carboxylic dianhydride is used. The film surfaces are characterized by reflective high energy electron diffraction and atomic force microscopy. They show amorphous and polycrystalline film with smooth to rough surface appearance depending on substrate and growth condition.The second part is an ultra violet photoemission study of thin films of copper phtalocyanine (CuPc) deposited on two differently treated indium tin oxide (ITO) substrates, wet treated or wet treated and subsequently heated respectively. Thin films of CuPc are commonly used in OLED\u27s as a hole injection layer. Both the electronic properties of the substrate and the CuPc are found to depend on the substrate treatment. Specifically we find that the ITO workfunction is increased ~0.4-0.6 eV after heating, and that the highest occupied molecular orbital (HOMO) is shifted ~0.5 eV to a lower binding energy on the heated substrate. The shift in HOMO is interpreted as different Fermi level pinning at a spin split Cu derived orbital on the two surfaces.Finally three different fluorescent dopants are investigated in a standard OLED structure, 9,10-bis(phenyl-ethenyl)anthracene (BPEA), Zincporphyrin (ZnP), and Porhyrin (H2P). Current-voltage measurements show that BPEA doping increases the turn-on voltage whereas it remains the same for ZnP and H2P devices. Electroluminescence spectra show that BPEA has little effect on the emission spectra while ZnP and H2P doping result in a clear change with an almost complete energy transfer for the latter.Keywords: molecular semiconductors, OLED, evaporation deposition, CuPc, PTCD

Porphyrin doping of Alq3 for electroluminescence

Organic light emitting devices based on tris(8-hydroxyquinoline)aluminium (Alq3) doped with two fluorescent porphyrin derivatives,5,15-diphenyl-2,8,12,18-tetraethyl-3,7,13,17-tetramethylporphyrin and the corresponding zinc metalated one, were fabricated. As a consequence,the light emission changed, from standard green light from Alq3, to reddish and yellowish white respectively. The differentspectral content in the two cases indicates a possible route to a white light emitter, based on several dopants from the same family ofmolecules with different central atoms. The turn-on voltage of the devices was not increased by the doping

Organic molecular beam deposition system and initial studies of organic layer growth

This work describes an organic molecular beam deposition system with substrate entry/exitchamber, buffer chamber and with the possibility to transfer substrate from a III–V molecularbeam deposition system. Flux calibrations of organic molecules and the initial growth oforganic layers are described. For this purpose, the molecules 3,4,9,10 perylene tetra carboxylicdianhydride and copper phtalocyanine were used. Layers were grown on oxidized andhydrogen passivated Si(100), Indium tin oxide and glass respectively. The growth wasinvestigated with atomic force microscopy, reflection high energy electron diffraction andultraviolet photoemission spectroscopy. An investigation with x-ray photoelectron and Ramanspectroscopy on the effect of atmospheric exposure is also included, showing little effect ofsurface pollution when the samples were handled carefully. The initial formation (monolayers)of copper phtalocyanine thin films was studied by ultraviolet photoemission spectroscopy