Introduction
The neurotrophin system plays a pivotal role in the development, morphology, and survival of the nervous system, and its dysregulation has been manifested in numerous neurodegenerative ...and neuroinflammatory diseases. Neurotrophins NGF and BDNF are major growth factors that prevent neuronal death and synaptic loss through binding with high affinity to their specific tropomyosin-related kinase receptors namely, TrkA and TrkB, respectively. The poor pharmacokinetic properties prohibit the use of neurotrophins as therapeutic agents. Our group has previously synthesized BNN27, a prototype small molecule based on dehydroepiandrosterone, mimicking NGF through the activation of the TrkA receptor.
Methods
To obtain a better understanding of the stereo-electronic requirements for selective activation of TrkA and TrkB receptors, 27 new dehydroepiandrosterone derivatives bearing a C17-spiro-dihydropyran or cyclobutyl moiety were synthesized. The new compounds were evaluated for their ability (a) to selectively activate the TrkA receptor and its downstream signaling kinases Akt and Erk1/2 in PC12 cells, protecting these cells from serum deprivation-induced cell death, and (b) to induce phosphorylation of TrkB and to promote cell survival under serum deprivation conditions in NIH3T3 cells stable transfected with the TrkB receptor and primary cortical astrocytes. In addition the metabolic stability and CYP-mediated reaction was assessed.
Results
Among the novel derivatives, six were able to selectively protect PC12 cells through interaction with the TrkA receptor and five more to selectively protect TrkB-expressing cells via interaction with the TrkB receptor. In particular, compound ENT-A025 strongly induces TrkA and Erk1/2 phosphorylation, comparable to NGF, and can protect PC12 cells against serum deprivation-induced cell death. Furthermore, ENT-A065, ENT-A066, ENT-A068, ENT-A069, and ENT-A070 showed promising pro-survival effects in the PC12 cell line. Concerning TrkB agonists, ENT-A009 and ENT-A055 were able to induce phosphorylation of TrkB and reduce cell death levels in NIH3T3-TrkB cells. In addition, ENT-A076, ENT-A087, and ENT-A088 possessed antiapoptotic activity in NIH-3T3-TrkB cells exclusively mediated through the TrkB receptor. The metabolic stability and CYP-mediated reaction phenotyping of the potent analogs did not reveal any major liabilities.
Discussion
We have identified small molecule selective agonists of TrkA and TrkB receptors as promising lead neurotrophin mimetics for the development of potential therapeutics against neurodegenerative conditions.
A diastereoselective one pot five-component reaction toward the synthesis of 4-(tetrazole)-1,3-oxazinanes has been reported. The sonication-accelerated, catalyst-free, simple, general and highly time ...efficient, Asinger-Ugi-tetrazole reaction was used for the synthesis of diverse 4-(tetrazole)-1,3-oxazinanes. The reaction exhibit excellent diastereoselectivity and broad substrate scope.
Full text
Available for:
IJS, KILJ, NUK, UL, UM, UPUK
Abstract
Acetylation of histones and additional nuclear proteins is a key mechanism in the regulation of gene expression. Aberrant acetylation has been linked to a wide range of diseases including ...cancer, inflammation, and neurodevelopmental disorders. Histone acetylation is introduced by histone acetyltransferases complexes (HATs), where substrate specificity is dramatically enhanced by scaffolding proteins that activate and target them to specific chromatin sites. A protein of interest with both epigenetic acetyl reader and scaffolding function is the protein Bromodomain and PHD finger-containing protein 1 (BRPF1). The Protein contains domains of two plant homeodomain (PHD) fingers separated by a zinc knuckle (PZP domain), a bromodomain, and a proline-tryptophan-tryptophan-proline (PWWP) Tudor domain. Native BRPF1 complexes can contain either MOZ/MORF or HBO1 as the catalytic MYST-family acetyltransferase subunit and the stable complex with Moz-Tif2 is known to lead to the development of human acute myeloid leukemia (AML). Given this, we chose to pursue the development of BRPF1 degraders to probe cancer disease biology especially in AML, where new therapies are required to overcome several unmet needs such as less-toxic treatments and relapsed/refractory disease paradigms. Here we present the design and synthesis of a range of BRPF1 degraders in highly desirable physicochemical space utilizing in-silico modeling. The prepared degraders which utilize multiple E3 ligases were then screened against cell lines harboring Mixed-lineage leukemia (MLL) translocations specifically the THP-1 cell line. In addition to this, we investigated the ability of the compounds to effectively degrade the target and suitability of our degraders for potential in-vivo exposure through a panel of routine ADMET assays.
Citation Format: Daniel Joseph Glynn, Rosie Crampton, Thomas Pesnot, Andrew Scott, Anne-Chloe Nassoy, Ralph Kirk, Daniele Narducci, Gary Nelson, Lynette Ongiri, Habiba Begum, Vincent Rao, Matilda Bingham, Rhoanne McPherson, Darryl Turner. The development of BRPF1 degraders as a potential treatment for acute myeloid leukemia abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 419.
A diastereoselective one pot five-component reaction toward the synthesis of 4-(tetrazole)-1,3-oxazinanes has been reported. The sonication-accelerated, catalyst-free, simple, general and highly time ...efficient, Asinger-Ugi-tetrazole reaction was used for the synthesis of diverse 4-(tetrazole)-1,3-oxazinanes. The reaction exhibit excellent diastereoselectivity and broad substrate scope.
A diastereoselective one pot five-component reaction toward the synthesis of 4-(tetrazole)-1,3-oxazinanes has been reported.
Full text
Available for:
IJS, KILJ, NUK, UL, UM, UPUK
This study introduces a method for the characterization of the magnetoelectric coupling in nanoscale Pb(Zr,Ti)O3/CoFeB thin film composites based on propagating spin-wave spectroscopy. Finite element ...simulations of the strain distribution in the devices indicated that the magnetoelastic effective field in the CoFeB waveguides was maximized in the Damon - Eshbach configuration. All-electrical broadband propagating spin-wave transmission measurements were conducted on Pb(Zr,Ti)O3/CoFeB magnetoelectric waveguides with lateral dimensions down to 700 nm. The results demonstrated that the spin-wave resonance frequency can be modulated by applying a bias voltage to Pb(Zr,Ti)O3. The modulation is hysteretic due to the ferroelastic behavior of Pb(Zr,Ti)O3. An analytical model was then used to correlate the change in resonance frequency to the induced magnetoelastic field in the magnetostrictive CoFeB waveguide. We observe a hysteresis magnetoelastic field strength with values as large as 5.61 mT, and a non-linear magnetoelectric coupling coefficient with a maximum value of 1.69 mT/V.
The parametric excitation of spin waves by coherent surface acoustic waves is demonstrated experimentally in metallic magnetic thin film structures. The involved magnon modes are analyzed with ...micro-focused Brillouin light scattering spectroscopy and complementary micromagnetic simulations combined with analytical modelling are used to determine the origin of the spin-wave instabilities. Depending on the experimental conditions, we observe spin-wave instabilities originating from different phonon-magnon and magnon-magnon scattering processes. Our results demonstrate that an efficient excitation of high amplitude, strongly nonlinear magnons in metallic ferromagnets is possible by surface acoustic waves, which opens novel ways to create micro-scaled nonlinear magnonic systems for logic and data processing that can profit from the high excitation efficiency of phonons using piezoelectricity.
Spin waves modes in magnetic waveguides with width down to 320 nm have been studied by electrical propagating spin-wave spectroscopy and micromagnetic simulations for both longitudinal and transverse ...magnetic bias fields. For longitudinal bias fields, a 1.3 GHz wide spin-wave band was observed in agreement with analytical dispersion relations for uniform magnetization. However, transverse bias field led to several distinct bands, corresponding to different quantized width modes, with both negative and positive slopes. Micromagnetic simulations showed that, in this geometry, the magnetization was nonuniform and tilted due to the strong shape anisotropy of the waveguides. Simulations of the quantized spin-wave modes in such nonuniformly magnetized waveguides resulted in spin wave dispersion relations in good agreement with the experiments.
We report on the resonant excitation of spin waves in micro-structured magnetic thin films by surface acoustic waves (SAWs). The spin waves as well as the acoustic waves are studied by micro-focused ...Brillouin light scattering spectroscopy. Besides the excitation of the ferromagnetic resonance, a process which does not fulfill momentum conservation, also the excitation of finite-wavelength spin waves can be observed at low magnetic fields. Using micromagnetic simulations, we verify that during this excitation both energy and linear momentum are conserved and fully transferred from the SAW to the spin wave.
PDF
