Nav1.7 Modulator Bearing a 3-Hydroxyindole Backbone Holds the Potential to Reverse Neuropathic Pain.

Chronic pain is a growing global health problem affecting at least 10% of the world's population. However, current chronic pain treatments are inadequate. Voltage-gated sodium channels (Navs) play a pivotal role in regulating neuronal excitability and pain signal transmission and thus are main targets for nonopioid painkiller development, especially those preferentially expressed in dorsal root ganglial (DRG) neurons, such as Nav1.6, Nav1.7, and Nav1.8. In this study, we screened in virtual hits from dihydrobenzofuran and 3-hydroxyoxindole hybrid molecules against Navs via a veratridine (VTD)-based calcium imaging method. The results showed that one of the molecules, 3g, could inhibit VTD-induced neuronal activity significantly. Voltage clamp recordings demonstrated that 3g inhibited the total Na+ currents of DRG neurons in a concentration-dependent manner. Biophysical analysis revealed that 3g slowed the activation, meanwhile enhancing the inactivation of the Navs. Additionally, 3g use-dependently blocked Na+ currents. By combining with selective Nav inhibitors and a heterozygous expression system, we demonstrated that 3g preferentially inhibited the TTX-S Na+ currents, specifically the Nav1.7 current, other than the TTX-R Na+ currents. Molecular docking experiments implicated that 3g binds to a known allosteric site at the voltage-sensing domain IV(VSDIV) of Nav1.7. Finally, intrathecal injection of 3g significantly relieved mechanical pain behavior in the spared nerve injury (SNI) rat model, suggesting that 3g is a promising candidate for treating chronic pain.

A copper-catalyzed three-component reaction of dithioacetals with diazo ketones and ketimines.

A copper-catalyzed three-component reaction of dithioacetals with diazo-ketones and ketimines has been reported. This reaction proceeds via trapping of the highly active sulfur ylide species, which are generated from thioacetal and carbene intermediates, with isatin-derived ketimine, providing an efficient protocol for the synthesis of acyclic thioacetal derivatives and medium-sized sulfur-containing heterocycles in good to high yields under mild reaction conditions with a broad substrate scope.

Diastereoselective aldol-type interception of phenolic oxonium ylides for the direct assembly of 2,2-disubstituted dihydrobenzofurans.

A Rh2(OAc)4 catalyzed intermolecular aldol-type interception of phenolic oxonium ylides with isatins has been developed, which provides an effective access to 2,2-disubstituted dihydrobenzofuran derivatives containing 3-hydroxyoxindole in high yields and with high diastereoselectivities under mild reaction conditions. The antiproliferation activity of these synthesized dihydrobenzofuran and 3-hydroxyoxindole hybrid products has been tested via the CCK8 assay in different cancer cell lines; compounds 3s and 3t exhibit good anticancer potency against human colon cancer cells (HCT116 cells, 3s: IC50 = 15.99 µM; 3t: IC50 = 14.48 µM) compared to other tested compounds.