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C25H33N10O7V2, triclinic, P1‾ $P\overline{1}$ (no. 2), a = 10.3933(4) Å, b = 12.5655(5) Å, c = 14.1841(5) Å, α = 65.373(1)°, β = 70.351(1)∘ $70.351{(1)}^{\circ }$ , γ = 88.052(2)∘ $88.052{(2)}^{\circ }$ , V = 1573.62(11) Å3, Z = 2, R gt(F) = 0.0362, wR ref(F 2) = 0.0885, T = 173 K.

KRAS mutations are highly prevalent in a wide range of lethal cancers, and these mutant forms of KRAS play a crucial role in driving cancer progression and conferring resistance to treatment. While there have been advancements in the development of small molecules to target specific KRAS mutants, the presence of undruggable mutants and the emergence of secondary mutations continue to pose challenges in the clinical treatment of KRAS-mutant cancers. In this study, we developed a novel molecular tool called tumor-targeting KRAS degrader (TKD) that effectively targets a wide range of KRAS mutants. TKD is composed of a KRAS-binding nanobody, a cell-penetrating peptide selectively targeting cancer cells, and a lysosome-binding motif. Our data revealed that TKD selectively binds to KRAS in cancer cells and effectively induces KRAS degradation via a lysosome-dependent process. Functionally, TKD suppresses tumor growth with no obvious side effects and enhances the antitumor effects of PD-1 antibody and cetuximab. This study not only provides a strategy for developing drugs targeting "undruggable" proteins but also reveals that TKD is a promising therapeutic for treating KRAS-mutant cancers. [ABSTRACT FROM AUTHOR]

Chemoresistance is a main reason for treatment failure in patients with nasopharyngeal carcinoma, but the exact regulatory mechanism underlying chemoresistance in nasopharyngeal carcinoma remains to be elucidated. Here, we identify PJA1 as a key E3 ubiquitin ligase involved in nasopharyngeal carcinoma chemoresistance that is highly expressed in nasopharyngeal carcinoma patients with nonresponse to docetaxel-cisplatin-5-fluorouracil induction chemotherapy. We find that PJA1 facilitates docetaxel resistance by inhibiting GSDME-mediated pyroptosis in nasopharyngeal carcinoma cells. Mechanistically, PJA1 promotes the degradation of the mitochondrial protein PGAM5 by increasing its K48-linked ubiquitination at K88, which further facilitates DRP1 phosphorylation at S637 and reduced mitochondrial reactive oxygen species production, resulting in suppression of GSDME-mediated pyroptosis and the antitumour immune response. PGAM5 knockdown fully restores the docetaxel sensitization effect of PJA1 knockdown. Moreover, pharmacological targeting of PJA1 with the small molecule inhibitor RTA402 enhances the docetaxel sensitivity of nasopharyngeal carcinoma in vitro and in vivo. Clinically, high PJA1 expression indicates inferior survival and poor clinical efficacy of TPF IC in nasopharyngeal carcinoma patients. Our study emphasizes the essential role of E3 ligases in regulating chemoresistance and provides therapeutic strategies for nasopharyngeal carcinoma based on targeting the ubiquitin-proteasome system. While chemotherapy may initially be effective in patient with nasopharyngeal carcinoma (NPC), resistance often develops. Here, the authors identify PJA1 as a driver of resistance to docetaxel via inhibition of GSDME-mediated proptosis and target this using a PJA1 inhibitor to restore sensitivity in preclinical models of NPC. [ABSTRACT FROM AUTHOR]

Four kinds of tridentate [OSO] bisphenol titanium complex catalysts [S (2-CH2-4-tBu-6-R-C6H2O)2]TiCl2(R1 = CMe3, R2 = CPhMe2, R3 = CPh2Me, R4 = CPh3) were prepared from 4-tert-butyl phenol through bromination, nucleophilic substitution and metal complexation reaction by changing the ortho-substituent of hydroxyl. The reaction performance of ethylene polymerization was investigated under the conditions of 30, 50, 70 °C, and pressure of 0.6 MPa. Polyolefin products under different conditions were obtained by changing the Al/Ti ratio of the catalyst and the reaction time. The products were characterized and analyzed by gel chromatogram phy (GPC). The four catalysts under different reaction conditions were compared. Due to the effect of R group steric hindrance, the larger the steric hindrance, the higher the activity of the catalyst. Based on the experimental results, it was concluded that the activity of the [S(2-CH2-4-tBu-6-CMePh2-C6H2O)2]TiCl2 catalyst at 50 °C was up to 6.7 x 106 g PE/(mol Ti ⋅ h), and the obtained polyolefin product Mw was 1.68 x 105, with a molecular weight distribution of 3.2. [ABSTRACT FROM AUTHOR]

C25H33N10O7V2, triclinic, P 1 ‾ (no. 2), a = 10.3933(4) Å, b = 12.5655(5) Å, c = 14.1841(5) Å, α = 65.373(1)°, β = 70.351 (1) ∘ , γ = 88.052 (2) ∘ , V = 1573.62(11) Å3, Z = 2, Rgt(F) = 0.0362, wRref(F2) = 0.0885, T = 173 K. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: A visible‐light‐induced tandem radical intramolecular cyclization/arylation of quinoxalin‐2(1H)‐ones with bromodifluoroacetamides is described. This protocol allows efficient access to a variety of valuable α,α‐difluoro‐γ‐lactam‐fused quinoxalin‐2(1H)‐ones in moderate to good yields under metal‐free, mild and redox neutral reaction conditions. This strategy is tolerant of various functional groups and a broad range of substrates. The mechanism experiments suggested an involvement of 5‐exo‐trig cyclization and a radical process in this transformation. [ABSTRACT FROM AUTHOR]

This work reports the photocatalytic application of an anthraquinone‐containing polymeric photosensitizer (AQ‐PHEMA) in the visible light‐induced cross‐dehydrogenative‐coupling of N‐aryl tetrahydroisoquinolines with several nucleophiles, including nitromethane, 1‐methyl‐2‐alkyl ketone and dialkyl (aryl) phosphine oxide. The results revealed that the reaction could be catalyzed by AQ‐PHEMA efficiently to afford a series of 1‐substituted‐2‐aryl‐1,2,3,4‐tetrahydroisoquinolines in good to excellent yields with nice substrate tolerance under aerobic conditions at room temperature. The practical application potential was also showcased by a gram‐scale synthesis. More importantly, the utilization of AQ‐PHEMA as a heterogeneous photosensitizer also showed nice recyclability and reusability of the catalyst, whereas AQ‐PHEMA can be easily separated and reused for at least 8 times without significant loss of photocatalytic activity. [ABSTRACT FROM AUTHOR]

C25H33N10O7V2, triclinic, P 1 ‾ (no. 2), a = 10.3933(4) Å, b = 12.5655(5) Å, c = 14.1841(5) Å, α = 65.373(1)°, β = 70.351 (1) ∘ , γ = 88.052 (2) ∘ , V = 1573.62(11) Å3, Z = 2, Rgt(F) = 0.0362, wRref(F2) = 0.0885, T = 173 K. [ABSTRACT FROM AUTHOR]

Brown carbon (BrC) refers to a group of organic compounds in fine atmospheric particles (PM 2.5 ) that are able to absorb light in the ultraviolet and visible range. They have a significant impact on the visibility of air and on the earth's climate. In this study, we used a black carbon analyzer (Model AE33) to conduct field measurements in northern suburban Nanjing from March 2021 to February 2022. We measured the light absorption coefficients of BrC in PM 2.5 and quantified the contributions of primary (BrC pri ) and secondary brown carbon (BrC sec ) in BrC by using the minimum correlation method (MRS), combined with the backward trajectories,potential source contribution function (PSCF) analysis, and diurnal patterns to analyze the seasonal characteristics of BrC. The results showed that the annual average light absorption of BrC was(7.76±7.17)Mm -1 (at 370 nm), and its contribution to the total aerosol light absorption was (22.0±8.8)%. BrC light absorption at different wavelengths all showed a U-shape seasonal variation of high in spring and winter and low in summer and fall. MRS analysis showed that the annual average contributions of BrC pri and BrC sec were (62.9±21.4)% and (37.1±21.4)% (at 370 nm), respectively; however, the contribution of BrC sec increased with the increase in wavelength, and it became dominant in longer wavelengths such as 660 nm. Backward trajectory and PSCF analysis showed that BrC was heavily influenced by air masses from the sea in spring, summer, and fall but was influenced greatly by local and regional continental emissions in winter. Traffic emissions in spring, summer, and fall were more intense to contribute to BrC pri than that in winter, whereas coal and biomass combustion had a greater impact on BrC pri in winter. Detailed analysis revealed that gas-phase photochemistry and aqueous chemistry had different influences on BrC sec formation in different seasons. It was mainly from gas-phase photochemistry in summer but was dominated by aqueous process in winter; both processes, however, were important pathways to BrC sec in spring and fall.

This work reports the photocatalytic application of an anthraquinone-containing polymeric photosensitizer (AQ-PHEMA) in the visible light-induced cross-dehydrogenative-coupling of N-aryl tetrahydroisoquinolines with several nucleophiles, including nitromethane, 1-methyl-2-alkyl ketone and dialkyl (aryl) phosphine oxide. The results revealed that the reaction could be catalyzed by AQ-PHEMA efficiently to afford a series of 1-substituted-2-aryl-1,2,3,4-tetrahydroisoquinolines in good to excellent yields with nice substrate tolerance under aerobic conditions at room temperature. The practical application potential was also showcased by a gram-scale synthesis. More importantly, the utilization of AQ-PHEMA as a heterogeneous photosensitizer also showed nice recyclability and reusability of the catalyst, whereas AQ-PHEMA can be easily separated and reused for at least 8 times without significant loss of photocatalytic activity., (© 2021 Wiley-VCH GmbH.)