Diversity Synthesis of Complex Pyridines Yields a Probe of a Neurotrophic Signaling Pathway

Abstract

Recognizing the value of including complex pyridines in small-molecule screening collections, we developed a previously unexplored [2 + 2 + 2]-cycloaddition of silyl-tethered diynes with nitriles. The tether provides high regioselectivity, while the solvent THF allows catalytic CpCo(CO)2 to be used without exogenous irradiation. One of the resulting bicyclic and monocyclic (desilylated) pyridines was identified as an inhibitor of neuregulin-induced neurite outgrowth (EC50 = 0.30 µM) in a screen that probes a pathway likely to be involved in breast cancers and schizophrenia.

Chemical Genetics Identifies Small-Molecule Modulators of Neuritogenesis Involving Neuregulin-1/ErbB4 Signaling

“…In addition, expanded screening of libraries of known bioactives, purified natural products, F.D.A.-approved drugs, and products of diversity-oriented synthesis using the system described here could also yield other useful chemical tools and improve in-depth understanding of Nrg1-mediated neurotrophic processes. As an example, our recent description of a potent pyridine-containing molecule (Cpd-52), which potently (EC 50 = 300nM) inhibited Nrg1-induced neurite outgrowth (51). Further investigation of the electrophysiological and biochemical effects of the compounds identified in this study, along with target identification and more in depth exploration of the underlying structure-activity relationships, would provide important insight into the role of Nrg1 in regulating neural circuitry.…”

Chemical probes and drug leads from advances in synthetic planning and methodology

“…80,260 The benzannulated sultam 4 modulates lysosome acidification and thus serves as a probe for V-ATPase function, 75 which has been associated with loss of bone density and decreased kidney function, among other conditions. 261,262 Other compounds interact with targets implicated in Alzheimer’s disease ( 1 ), 71 holoprosencephaly ( 2 ), 72 schizophrenia ( 3 ), 74 inflammatory diseases ( 5 ), 76 lipid metabolism ( 6 ), 79 and coronary artery disease ( 8 ) 81 . The remaining compounds shown are described in more detail in the vignettes in the main text.…”

Transition Metal-Mediated Synthesis of Monocyclic Aromatic Heterocycles

“…738 The reaction tolerates a variety of aliphatic and aromatic nitriles, providing pyridine derivatives 6-166 in regioselective fashion. Notably, the Si-tether can be removed from the products 6-166 to produce pyridines 6-167 efficiently.…”