Pyrazoles are important azole heteroarenes frequently found in pharmaceuticals and protein ligands and there has been a growing interest in new synthetic methods for their preparation. We report the first catalytic intermolecular C-H arylation of pyrazoles, namely SEM-protected pyrazoles and N-alkylpyrazoles, which lays the foundation for a new approach to the synthesis of complex arylated pyrazoles, where new arene rings are directly attached to predetermined positions of the heteroarene nucleus. Through a systematic search we identified a palladium-pivalate catalytic system as the most effective protocol and mapped the reactivity of all three C-H bonds of the pyrazole (C-5 > C-4 ≫ C-3). To circumvent the low reactivity of C-3 position, we developed a “SEM switch”, which transposes the SEM-protecting group from one nitrogen to the other in one step, and in the process transforms the unreactive C-3 position to the reactive C-5 position. The SEM switch thus enables sequential arylation of C-5 and C-3 position, providing rapid access to protected or free 3,4,5-triarylpyrazoles (C-4 arene ring is readily introduced by bromination and Suzuki coupling). Furthermore, N-alkylation of SEM-protected pyrazoles allows for regioselective introduction of the amine substituent, addressing the low regioselectivity of N-alkylation of pyrazoles lacking sufficient steric bias. Thus, the catalytic C-H arylation combined with the protecting group transposition and N-alkylation provides a rapid route to fully substituted pyrazoles with complete regiocontrol of all substituents. The particular strength of this strategy is the ability to commence the synthesis from either the parent pyrazole or practically any pyrazole intermediate.
Brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related kinase B (TrkB), have emerged as key regulators of brain plasticity and represent disease-modifying targets for several brain disorders, including Alzheimer's disease and major depressive disorder. Because of poor pharmacokinetic properties of BDNF, the interest in small-molecule TrkB agonists and modulators is high. Several compounds have been reported to act as TrkB agonists, and their increasing use in various nervous system disorder models creates the perception that these are reliable probes. To examine key pharmacological parameters of these compounds in detail, we have developed and optimized a series of complementary quantitative assays that measure TrkB receptor activation, TrkB-dependent downstream signaling, and gene expression in different cellular contexts. Although BDNF and other neurotrophic factors elicited robust and dose-dependent receptor activation and downstream signaling, we were unable to reproduce these activities using the reported small-molecule TrkB agonists. Our findings indicate that experimental results obtained with these compounds must be carefully interpreted and highlight the challenge of developing reliable pharmacological activators of this key molecular target.
Modulation of growth factor signaling pathways in the brain represents a new experimental approach to treating neuropsychiatric disorders such as depression, anxiety, and addiction. Neurotrophins and growth factors exert synaptic, neuronal, and circuit level effects on a wide temporal range, which suggests a possibility of rapid and lasting therapeutic effects. Consequently, identification of small molecules that can either enhance the release of growth factors or potentiate their respective pathways will provide a drug-like alternative to direct neurotrophin administration or viral gene delivery and thus represents an important frontier in chemical biology and drug design. Glial cell line-derived neurotrophic factor (GDNF), in particular, has been implicated in marked reduction of alcohol consumption in rodent addiction models, and the natural product ibogaine, a substance used traditionally in ritualistic ceremonies, has been suggested to increase the synthesis and release of GDNF in the dopaminergic system in rats. In this report, we describe a novel iboga analog, XL-008, created by unraveling the medium size ring of the ibogamine skeleton, and its ability to induce release of GDNF in C6 glioma cells. Additionally, XL-008 potentiates the release of GDNF induced by fibroblast growth factor 2 (FGF2), another neurotrophin implicated in major depressive disorder, increasing potency more than 2-fold (from 7.85 ± 2.59 ng/mL to 3.31 ± 0.98 ng/mL) and efficacy more than 3-fold. The GDNF release by both XL-008 and the FGF2/XL-008 mixture was found to be mediated through the MEK and PI3K signaling pathways but not through PLCγ in C6 glioma cells.
abled by SEM-Group Transposition. -Key to this selective arylation of pyrazoles is the SEM-group transposition from one nitrogen to the other which transforms the unreactive C-3 position to the reactive C-5 position. This change in reactivity is also achieved by N-methylation/deprotection. -(GOIKHMAN, R.; JACQUES, T. L.; SAMES*, D.; J. Am. Chem. Soc. 131 (2009) 8, 3042-3048; Dep. Chem., Columbia Univ., New York, NY 10027, USA; Eng.) -Nuesgen 28-103
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