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Developing methods to directly transform C(sp3) −H bonds is crucial in synthetic chemistry due to their prevalence in various organic compounds. While conventional protocols have largely relied on transition metal catalysis, recent advancements in organocatalysis, particularly with radical NHC catalysis have sparked interest in the direct functionalization of "inert" C(sp3) −H bonds for cross C−C coupling with carbonyl moieties. This strategy involves selective cleavage of C(sp3) −H bonds to generate key carbon radicals, often achieved via hydrogen atom transfer (HAT) processes. By leveraging the bond dissociation energy (BDE) and polarity effects, HAT enables the rapid functionalization of diverse C(sp3)−H substrates, such as ethers, amines, and alkanes. This mini‐review summarizes the progress in carbene organocatalytic functionalization of inert C(sp3)−H bonds enabled by HAT processes, categorizing them into two sections: 1) C−H functionalization involving acyl azolium intermediates; and 2) functionalization of C−H bonds via reductive Breslow intermediates. [ABSTRACT FROM AUTHOR]

The direct functionalization of inert C(sp3)‐H bonds to form carbon‐carbon and carbon‐heteroatom bonds offers vast potential for chemical synthesis and therefore receives increasing attention. At present, most successes come from strategies using metal catalysts/reagents or photo/electrochemical processes. The use of organocatalysis for this purpose remains scarce, especially when dealing with challenging C−H bonds such as those from simple alkanes. Here we disclose the first organocatalytic direct functionalization/acylation of inert C(sp3)‐H bonds of completely unfunctionalized alkanes. Our approach involves N‐heterocyclic carbene catalyst‐mediated carbonyl radical intermediate generation and coupling with simple alkanes (through the corresponding alkyl radical intermediates generated via a hydrogen atom transfer process). Unreactive C−H bonds are widely present in fossil fuel feedstocks, commercially important organic polymers, and complex molecules such as natural products. Our present study shall inspire a new avenue for quick functionalization of these molecules under the light‐ and metal‐free catalytic conditions. [ABSTRACT FROM AUTHOR]

The gene mutations of LRRK2, which encodes leucine‐rich repeat kinase 2 (LRRK2), are associated with one of the most prevalent monogenic forms of Parkinson's disease (PD). However, the potential effectors of the Gly2019Ser (G2019S) mutation remain unknown. In this study, the authors investigate the effects of LRRK2 G2019S on endoplasmic reticulum (ER) stress in induced pluripotent stem cell (iPSC)‐induced dopamine neurons and explore potential therapeutic targets in mice model. These findings demonstrate that LRRK2 G2019S significantly promotes ER stress in neurons and mice. Interestingly, inhibiting LRRK2 activity can ameliorate ER stress induced by the mutation. Moreover, LRRK2 mutation can induce ER stress by directly interacting with thrombospondin‐1/transforming growth factor beta1 (THBS1/TGF‐β1). Inhibition of LRRK2 kinase activity can effectively suppress ER stress and the expression of THBS1/TGF‐β1. Knocking down THBS1 can rescue ER stress by interacting with TGF‐β1 and behavior burden caused by the LRRK2 mutation, while suppression of TGF‐β1 has a similar effect. Overall, it is demonstrated that the LRRK2 mutation promotes ER stress by directly interacting with THBS1/TGF‐β1, leading to neural death in PD. These findings provide valuable insights into the pathogenesis of PD, highlighting potential diagnostic markers and therapeutic targets. [ABSTRACT FROM AUTHOR]

The development of catalyst‐controlled methods for direct functionalization of two distinct C−H bonds represents an appealing approach for C−C formations in synthetic chemistry. Herein, we describe an organocatalytic approach for straightforward acylation of C(sp3)−H bonds employing readily available aldehyde as "acyl source" involving dehydrogenative coupling of aldehydes with ether, amine, or benzylic C(sp3)−H bonds. The developed method affords a broad range of ketones under mild conditions. Mechanistically, simple ortho‐cyanoiodobenzene is essential in the oxidative radical N‐heterocyclic carbene catalysis to give a ketyl radical and C(sp3) radical through a rarely explored intermolecular hydrogen atom transfer pathway, rendering the acylative C−C formations in high efficiency under a metal‐ and light‐free catalytic conditions. Moreover, the prepared products show promising anti‐bacterial activities that shall encourage further investigations on novel agrochemical development. [ABSTRACT FROM AUTHOR]

Parkinson's disease ( PD) is the most prevalent movement disorder characterized by selective loss of midbrain dopaminergic ( DA) neurons. MicroRNA-124 (mi R-124) is abundantly expressed in the DA neurons and its expression level decreases in the 1-methyl-4-pheny-1, 2, 3, 6-tetrahydropyridine ( MPTP) model of PD. However, whether the upregulation of miR-124 could attenuate neurodegeneration remains unknown. Here, we employed miR-124 agomir and miR-124 mimics to upregulate mi R-124 expression in MPTP-treated mice and MPP+-intoxicated SH- SY5Y cells, respectively. We found that loss of DA neurons and striatal dopamine in MPTP-treated mice was significantly reduced by upregulating mi R-124. In addition, we identified a target of mi R-124, Bim that mediated the neuroprotection of mi R-124. Indeed, treatment of mi R-124 agomir in MPTP-treated mice inhibited Bim expression, thus suppressing Bax translocation to mitochondria. Moreover, impaired autophagy process in MPTP-treated mice and MPP+-intoxicated SH- SY5Y cells characterized as autophagosomes ( AP) accumulation and lysosomal depletion were alleviated by the upregulation of miR-124. Taken together, these results indicate that upregulation of mi R-124 could regulate apoptosis and impaired autophagy process in the MPTP model of PD, thus reducing the loss of DA neurons. [ABSTRACT FROM AUTHOR]