Targeting of REST with rationally-designed small molecule compounds exhibits synergetic therapeutic potential in human glioblastoma cells.

BACKGROUND: Glioblastoma (GBM) is an aggressive brain cancer associated with poor prognosis, intrinsic heterogeneity, plasticity, and therapy resistance. In some GBMs, cell proliferation is fueled by a transcriptional regulator, repressor element-1 silencing transcription factor (REST). RESULTS: Using CRISPR/Cas9, we identified GBM cell lines dependent on REST activity. We developed new small molecule inhibitory compounds targeting small C-terminal domain phosphatase 1 (SCP1) to reduce REST protein level and transcriptional activity in glioblastoma cells. Top leads of the series like GR-28 exhibit potent cytotoxicity, reduce REST protein level, and suppress its transcriptional activity. Upon the loss of REST protein, GBM cells can potentially compensate by rewiring fatty acid metabolism, enabling continued proliferation. Combining REST inhibition with the blockade of this compensatory adaptation using long-chain acyl-CoA synthetase inhibitor Triacsin C demonstrated substantial synergetic potential without inducing hepatotoxicity. CONCLUSIONS: Our results highlight the efficacy and selectivity of targeting REST alone or in combination as a therapeutic strategy to combat high-REST GBM.

Programmed synthesis of triarylnitroimidazoles via sequential cross-coupling reactions.

Transition-metal-catalyzed programmed sequential arylation reactions of 2-chloro-4-nitro-1H-imidazoles were achieved. The methods are general and were applied in a chemoselective manner for the synthesis of different multiarylated 4-nitroimidazoles bearing three different aryl groups. A salient feature is Pd-catalyzed hetero-hetero coupling at the C5 position through a NO2 directed cross-dehydrogenative coupling (CDC) approach.

Palladium-catalyzed aminocarbonylation of halo-substituted 7-azaindoles and other heteroarenes using chloroform as a carbon monoxide source.

A palladium-catalyzed aminocarbonylation of halo-substituted 7-azaindoles utilizing CHCl3 as the carbonyl source has been developed for the straightforward incorporation of an amide functional group. The protocol was extended to other heteroarenes such as pyrazolopyridines and indazoles. The substrate scope of the reaction with respect to heteroarenes and the amine component is reported. This method offers an alternative avenue for aminocarbonylation of pharmaceutically important heterocycles.

Cobalt-Catalyzed Regioselective Ortho C(sp2)-H Bond Nitration of Aromatics through Proton-Coupled Electron Transfer Assistance.

A cobalt-catalyzed proton-coupled electron transfer (PCET) mediated regioselective ortho-specific nitration of aromatic C(sp2)-H bonds using chelation-assisted removable vicinal diamine directing groups was developed. The reaction proceeded under mild conditions in the presence of Co(OAc)2·4H2O as the catalyst with AgNO2 utilized as the nitro source as well as terminal oxidant in the presence of O2 as an external oxidant. No external base or additives were required for this process. Controlled experiments and mechanistic investigations with DFT calculations revealed that the reaction proceeds through a PCET promoted nitro functional group transfer pathway. Moreover, the produced compounds are valuable and pharmaceutically quite relevant.

Divergent synthesis of 4,6-diarylated pyridin-2(1H)-ones from chalcones: novel access to 2,4,6-triaryl pyridines.

A wide range of 4,6-diarylated/heterylated pyridin-2(1H)-one derivatives were synthesized in good to excellent yields from 1,3-diarylated/heterylated-2-propen-1-ones (chalcones) in one pot under metal and base-free conditions. This domino reaction suggests a novel mechanism comprising of Michael addition followed by amination, subsequent intramolecular amidation and finally dehydronitrosation. The usefulness of the designed 4,6-diarylated/heterylated pyridin-2(1H)-one derivatives has further been demonstrated by synthesizing medicinally important 2,4,6-triaryl/heteryl pyridines via Pd-catalyzed cross-coupling reaction.