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The photoredox electron donor–acceptor (EDA) complex‐mediated radical coupling reaction has gained prominence in the field of organic synthesis, finding widespread application in two‐component coupling reactions. However, EDA complex‐promoted multi‐component reactions are not well developed with only a limited number of examples have been reported. Herein, we report a photoinduced and EDA complex‐promoted highly chemoselective three‐component radical arylalkylation of [1.1.1]propellane, which allows the direct functionalization of C(sp3)−H with bicyclo[1.1.1]pentanes (BCP)‐aryl groups under mild conditions. A variety of unnatural α‐amino acids, featuring structurally diversified 1,3‐disubstituted BCP moieties, were synthesized in a single‐step process. Notably, leveraging the high tension release of [1.1.1]propellane, the highly unstable transient aryl radical undergoes rapid conversion into a relatively stable tertiary alkyl transient radical, and consequently, the competing side‐reaction of two‐component coupling was entirely suppressed. The strategic use of this transient radical conversion approach would be useful for the design of diverse EDA complex‐mediated multi‐component reactions. It is noteworthy that the highly chemoselective late‐stage incorporation of the 1,3‐disubstituted BCP pharmacophores into peptides was achieved both in liquid‐phase and solid‐phase reactions. This advancement is anticipated to have significant application potential in the future development of peptide drugs. [ABSTRACT FROM AUTHOR]

Ischemic heart disease (IHD) remains a major global health concern, with ischemia-reperfusion injury exacerbating myocardial damage despite therapeutic interventions. In this study, we investigated the role of tropomyosin 3 (TPM3) in protecting cardiomyocytes against hypoxia-induced injury and oxidative stress. Using the AC16 and H9c2 cell lines, we established a chemical hypoxia model by treating cells with cobalt chloride (CoCl2) to simulate low-oxygen conditions. We found that CoCl2 treatment significantly upregulated the expression of hypoxia-inducible factor 1 alpha (HIF-1α) in cardiomyocytes, indicating the successful induction of hypoxia. Subsequent morphological and biochemical analyses revealed that hypoxia altered cardiomyocyte morphology disrupted the cytoskeleton, and caused cellular damage, accompanied by increased lactate dehydrogenase (LDH) release and malondialdehyde (MDA) levels, and decreased superoxide dismutase (SOD) activity, indicative of oxidative stress. Lentivirus-mediated TPM3 overexpression attenuated hypoxia-induced morphological changes, cellular damage, and oxidative stress imbalance, while TPM3 knockdown exacerbated these effects. Furthermore, treatment with the HDAC1 inhibitor MGCD0103 partially reversed the exacerbation of hypoxia-induced injury caused by TPM3 knockdown. Protein–protein interaction (PPI) network and functional enrichment analysis suggested that TPM3 may modulate cardiac muscle development, contraction, and adrenergic signaling pathways. In conclusion, our findings highlight the therapeutic potential of TPM3 modulation in mitigating hypoxia-associated cardiac injury, suggesting a promising avenue for the treatment of ischemic heart disease and other hypoxia-related cardiac pathologies. [ABSTRACT FROM AUTHOR]

Alkylnitriles play important roles in many fields because of their unique electronic properties and structural characteristics. Incorporating cyanoalkyl with characteristic spectroscopy and reactivity properties into amino acids and peptides is of special interest for potential imaging and therapeutic purposes. Here, we report a copper-catalyzed asymmetric cyanoalkylation of C(sp3)-H. In the reactions, glycine derivatives can effectively couple with various cycloalkanone oxime esters with high enantioselectivities, and the reaction can be applied to the late-stage modification of peptides with good yields and excellent stereoselectivities, which is useful for modern peptide synthesis and drug discovery. The mechanistic studies show that the in situ formed copper complex by the coordination of glycine derivatives and chiral phosphine Cu catalyst can not only mediate the single electronic reduction of cycloalkanone oxime ester but also control the stereoselectivity of the cyanoalkylation reaction. Incorporating cyanoalkyl moieties into amino acids and peptides is of interest for potential imaging and therapeutic purposes. Here, the authors developed a Cu-catalyzed asymmetric cyanoalkylation of glycine derivatives for the synthesis of α-cyanoalkylate amino acids and peptide modification. [ABSTRACT FROM AUTHOR]

Radical‐based reactions usually exhibit excellent functional‐group compatibilities due to their mild initiation conditions. Glycosyl radical involved C‐glycosylation modifications are important strategies to achieve highly regio‐ and chemoselective constructions of C‐glycosidic bonds or C‐glycoside linkages of peptides and proteins. In this Concept, we cover recent developments in glycosyl radical‐based synthesis of unnatural amino acids and late‐stage modification of peptides and proteins, and provide a preliminary outlook on the possible development of this direction in the future. [ABSTRACT FROM AUTHOR]

Herein, a non-classical C-saccharide linkage is reported via a C5 radical of pentose or C6 radical of hexose addition to Michael acceptors. C(sp3)–S cleaved glycosyl thianthrenium salts are developed as the glycosyl radical agents. The reaction provides an efficient toolkit to synthesize β-glycosyl substituted unnatural amino acids as well as for the late-stage C-saccharide modification of peptides. [ABSTRACT FROM AUTHOR]

Simple Summary: Due to the malignant features of glioma, current interventions result in limited treatment effects and poor prognoses for all patients. The functions of the tropomyosin (TPM) family in tumors and cancers have been explored. However, striking differences have been observed. This study aims to further our understanding of the effects of TPMs in glioma. Our study explored the expression and prognoses of TPM in glioma, as well as the gene functions of TPMs. High expression of TPM3 and TPM4 were positively correlated with poorer prognosis in glioma, and TPM3 could serve as a novel independent prognostic factor of glioma. (1) Background: The functions of the tropomyosin (TPM) family in tumors and cancers have been explored; however, striking differences have been observed. This study aims to further our understanding of the effects of TPMs in glioma, and find novel biomarkers for glioma. (2) Methods: RNA-seq data were downloaded from TCGA and GTEx. Survival analyses, Cox regression, nomogram, calibration curves, ROC curves, gene function enrichment analyses, and immune cell infiltration analyses were carried out using R. CCK8 assay, while Brdu assay, colony formation assay, and Transwell assay were used to verify the functions of TPM3 in glioma. (3) Results: TPM1/3/4 were significantly more highly expressed in glioma than that in normal tissues, while higher expression of TPM2/3/4 was correlated with a worse overall survival than lower expression of TPM2/3/4. Furthermore, bioinformatic analyses indicated that TPM3/4 could be promoting factors for poorer survival in glioma, but only TPM3 could serve as an independent prognostic factor. Gene function analyses showed that TPMs may be involved in immune responses. Moreover, further experimental investigations verified that TPM3 overexpression enhanced the proliferation and tumorigenicity of glioma. (4) Conclusions: High expression of TPM3/4 was positively correlated with poorer prognosis in glioma, and TPM3 could serve as a novel independent prognostic factor of glioma. [ABSTRACT FROM AUTHOR]

The glycosylative modification of peptides could improve the pharmacological properties of peptide drugs and deliver them efficiently to the target sites. Compared with O‐/N‐glycosides, C‐glycosides exhibit more metabolic stability. We here disclose the first example of visible‐light‐promoted and Cu‐catalyzed stereoselective C‐glycosylation. The mild reaction conditions are compatible with various carbohydrate substrates, as demonstrated with a series of monosaccharides and a disaccharide, and are amenable to the synthesis of a wide variety of C‐glycoamino acids and C‐glycopeptidomimetics with good yields and excellent stereoselectivities. The dual‐functional photocatalyst formed in situ via coordination of the glycine derivative and the chiral phosphine Cu complex could not only catalyze the photoredox process but also control the stereoselectivity of the glycosylation reaction. [ABSTRACT FROM AUTHOR]

Two‐dimensional semantics is probably the most significant development in contemporary philosophy of language. Among its various versions, it is Chalmers's epistemic two‐dimensionalism that received most widely discussions and most severe criticisms. Here I consider one such criticism, namely, "the nesting problem," which concerns the interaction between modality and apriority. I propose a solution to the problem and defend it through comparison with other approaches in the literature, as well as rebut with some potential objections. It turns out that my solution not only handles the interaction between modality and apriority naturally but also avoids many difficulties of other approaches. [ABSTRACT FROM AUTHOR]

The visible-light induced regioselective fluoroalkylfluoroalkylselenolation of unactivated alkenes was realized under metal and oxidant free conditions. The reaction was enabled by incorporation of two distinct photoinduced processes for the generation of two radical coupling partners. –CF3, –Rf, –CF2CO2Et, –CCl3, –SeCF3, and –SeRf were all successfully introduced to alkenes in good to excellent yields. The mild conditions showed a general substrate tolerance, and offered an efficient strategy for the late-stage functionalization of complex natural products and drug molecules. [ABSTRACT FROM AUTHOR]

Disclosed herein is the visible‐light‐promoted deaminative C(sp3)−H alkylation of glycine and peptides using Katritzky salts as electrophiles. Simple reaction conditions and excellent functional‐group tolerance provide a general strategy for the efficient preparation of unnatural α‐amino acids and precise modification of peptides with unnatural α‐amino‐acid residues. Mechanistic studies suggest that visible‐light‐promoted intermolecular charge transfer within a glycine–Katritzky salt electron donor‐acceptor (EDA) complex induces a single‐electron transfer process without the assistance of photocatalyst. [ABSTRACT FROM AUTHOR]

We here report the photoinduced Cu-catalyzed cyanoalkylation of electron-deficient alkenes by using alkyl bromides as alkylation reagents. In the reactions, 1°, 2°, and 3° unactivated alkyl bromides with various sensitive functional groups were well tolerated with good yields. Notably, terminal and internal alkenes, as well as alkene-containing peptides, were all tolerated well. [ABSTRACT FROM AUTHOR]

In this paper, I propose and defend a solution to Kripke's puzzle about time and thought, which lives in harmony with the axiom schema of separation and does not invoke paraconsistency. I also compare my solution with Parikh's semantic interpretation, and answer to three potential objections. [ABSTRACT FROM AUTHOR]

Despite a well‐developed and growing body of work in Cu catalysis, the potential of Cu to serve as a photocatalyst remains underexplored. Reported herein is the first example of visible‐light‐induced Cu‐catalyzed decarboxylative C(sp3)−H alkylation of glycine for preparing α‐alkylated unnatural α‐amino acids. It merits mentioning that the mild conditions and the good functional‐group tolerance allow the modification of peptides using this method. The mechanistic studies revealed that a radical–radical coupling pathway is involved in the reaction. Out of the clear blue: The title reaction was developed for preparing α‐alkylated non‐natural α‐amino acids by transformation of glycine moieties. Mild conditions and good functional‐group tolerance allow the modification of peptides using this method. Mechanistic studies revealed that a radical–radical coupling pathway is involved in the reaction. [ABSTRACT FROM AUTHOR]

In the past years, the activations of aromatic nitriles for radical arylations under photoirradiation have been developed. We here report the first example of radical arylations using aromatic nitriles without the assistance of photoirradiation. Importantly, with this method, the direct arylation of C(sp3)–H in benzyl amines provided a practical method for the synthesis of diarylmethylamines without the use of precious transition metal catalysts. [ABSTRACT FROM AUTHOR]

Abstract: The first visible‐light‐promoted dearomative fluoroalkylation of β‐naphthols was realized without the assistance of any transition‐metal catalysts or external photosensitizers. Inexpensive fluoroalkyl iodides were directly used as efficient fluoroalkylation reagents under very mild reaction conditions. The scope of this process was found to be general and broad, and both trifluoromethyl and perfluoroalkyl groups (‐C4F9, ‐C6F13, and ‐C8F17) were installed in excellent yields. Preliminary mechanistic studies suggest that visible‐light‐promoted intermolecular charge transfer within the naphtholate–fluoroalkyl iodide electron donor–acceptor (EDA) complex induces a single electron transfer in the absence of photocatalysts. [ABSTRACT FROM AUTHOR]

A traceless organosilicon template-directed meta-selective-C–H alkenylation of phenols was realized with good yields and high selectivities. The template was readily removable through F−-promoted O–Si cleavage under extremely mild conditions or recyclable through a p-TSA catalyzed process. The product was successfully applied in the preparation of a series of meta-alkenylated aromatic compounds. [ABSTRACT FROM AUTHOR]

In the past few years, Ru and Ir catalyzed photoredox radical coupling reactions have been widely applied in organic synthesis. In contrast, the applications of Cu catalysts in photoredox organic transformations were limited. We here report the first example of photoinduced, Cu-catalyzed three component cyanofluoroalkylation of alkenes by directly using fluoroalkyl iodides as fluoroalkylation reagents. [ABSTRACT FROM AUTHOR]

The article offersa the author's insights on the challenges of philosopher Timothy Williamson to the distinction between a posteriori and a priori. Topics mentioned include the top-down and bottom-up articulation, the consider on a priori-a posteriori distinction as epistemologically shallow, and the possiblility of the armchair knowledge with triple-distinction.

The functionalization of internal olefins has been a challenging task in organic synthesis. Efficient CuII-catalyzed trifluoromethylation of internal olefins, that is, α-oxoketene dithioacetals, has been achieved by using Cu(OH)2 as a catalyst and TMSCF3 as a trifluoromethylating reagent. The push-pull effect from the polarized olefin substrates facilitates the internal olefinic CH trifluoromethylation. Cyclic and acyclic dithioalkyl α-oxoketene acetals were used as the substrates and various substituents were tolerated. The internal olefinic CH bond cleavage was not involved in the rate-determining step, and a mechanism that involves radicals is proposed based on a TEMPO-quenching experiment of the trifluoromethylation reaction. Further derivatization of the resultant CF3 olefins led to multifunctionalized tetrasubstituted CF3 olefins and trifluoromethylated N-heterocycles. [ABSTRACT FROM AUTHOR]

It is widely accepted that knowledge is factive, but two different understandings of "factivity" should be distinguished, namely, the implication version and the presupposition version. While the former only takes the truth of P as a necessary requirement for "S knows that P," the latter considers it also necessary for "S does not know that P." In this paper, I argue against presupposition and defend implication. More specifically, I argue against Wang and Tai's defense of the presupposition version as presented in a recent paper and propose a pragmatic response to the "persistence problem" of implication. In other words, my positive proposal is an account of implication plus pragmatic implicature. To conclude, I use my version to analyze Wang and Tai's distinction between inner skepticism and outer skepticism. My conclusion is that, after abandoning presupposition, we can identify two types of intermediate skepticism between Wang and Tai's inner and outer skepticism. [ABSTRACT FROM AUTHOR]