Catalytic asymmetric construction of chiral indole‐fused rings has become an important issue in the chemical community because of the significance of such scaffolds. In this work, we have ...accomplished the first catalytic asymmetric (4+2) and (4+3) cycloadditions of 2,3‐indolyldimethanols by using indoles and 2‐naphthols as suitable reaction partners under the catalysis of chiral phosphoric acids, constructing enantioenriched indole‐fused six‐membered and seven‐membered rings in high yields with excellent enantioselectivities. In addition, this approach is used to realize the first enantioselective construction of challenging tetrahydroindolocarbazole scaffolds, which are found to show promising anticancer activity. More importantly, theoretical calculations of the reaction pathways and activation mode offer an in‐depth understanding of this class of indolylmethanols. This work not only settles the challenges in realizing catalytic asymmetric cycloadditions of indolyldimethanols but also provides a powerful strategy for the construction of enantioenriched indole‐fused rings.
The first catalytic asymmetric (4+2) and (4+3) cycloadditions of 2,3‐indolyldimethanols enable the construction of enantioenriched indole‐fused rings in high yields with excellent enantioselectivities. This approach led to the first enantioselective construction of challenging tetrahydroindolocarbazole scaffolds, which show promising anticancer activity. Theoretical calculations offer an in‐depth understanding of this class of indolylmethanols.
A new class of axially chiral styrene‐based thiourea tertiary amine catalysts, which have unique characteristics such as an efficient synthetic route, multiple chiral elements, and multiple ...activating groups, has been rationally designed. These new chiral catalysts have proven to be efficient organocatalysts, enabling the chemo‐, diastereo‐, and enantioselective (2+4) cyclization of 2‐benzothiazolimines with homophthalic anhydrides in good yields (up to 96 %) with excellent stereoselectivities (all >95:5 dr, up to 98 % ee). More importantly, theoretical calculations elucidated the important role of an axially chiral styrene moiety in controlling both the reactivity and enantioselectivity. This work not only represents the first design of styrene‐based chiral thiourea tertiary amine catalysts and the first catalytic asymmetric (2+4) cyclization of 2‐benzothiazolimines, but also gives an in‐depth understanding of axially chiral styrene‐based organocatalysts.
A new class of axially chiral styrene‐based organocatalysts has been rationally designed. They enable the chemo‐, diastereo‐ and enantioselective (2+4) cyclization of 2‐benzothiazolimines. This work represents the first design of styrene‐based chiral thiourea tertiary amine catalysts and the first catalytic asymmetric (2+4) cyclization of 2‐benzothiazolimines, and it gives an in‐depth understanding of axially chiral styrene‐based organocatalysts.
Catalytic hydrogenation or transfer hydrogenation of quinolines was thought to be a direct strategy to access dihydroquinolines. However, the challenge is to control the chemoselectivity and ...regioselectivity. Here we report an efficient partial transfer hydrogenation system operated by a cobalt-amido cooperative catalyst, which converts quinolines to 1,2-dihydroquinolines by the reaction with H
N·BH
at room temperature. This methodology enables the large scale synthesis of many 1,2-dihydroquinolines with a broad range of functional groups. Mechanistic studies demonstrate that the reduction of quinoline is controlled precisely by cobalt-amido cooperation to operate dihydrogen transfer from H
N·BH
to the N=C bond of the substrates.
A bis(pyridyl)amine‐bipyridine‐iron(II) framework (Fe(BPAbipy)) of complexes 1–3 is reported to shed light on the multistep nature of CO2 reduction. Herein, photocatalytic conversion of CO2 to CO ...even at low CO2 concentration (1 %), together with detailed mechanistic study and DFT calculations, reveal that 1 first undergoes two sequential one‐electron transfer affording an intermediate with electron density on both Fe and ligand for CO2 binding over proton. The following 2 H+‐assisted Fe‐CO formation is rate‐determining for selective CO2‐to‐CO reduction. A pendant, proton‐shuttling α‐OH group (2) initiates PCET for predominant H2 evolution, while an α‐OMe group (3) cancels the selectivity control for either CO or H2. The near‐unity selectivity of 1 and 2 enables self‐sorting syngas production at flexible CO/H2 ratios. The unprecedented results from one kind of molecular catalyst skeleton encourage insight into the beauty of advanced multi‐electron and multi‐proton transfer processes for robust CO2RR by photocatalysis.
A polypyridine Fe‐based skeleton is reported for selective CO2‐to‐CO photoreduction even under 1 % CO2. Mechanistic insights reveal two sequential one‐electron transfer affording an intermediate with delocalized electron density on both Fe and ligand for CO2 addition. Proton‐assisted CO formation is crucial for CO2 reduction. A pendant, proton‐shuttling α‐OH group switches the transformation to H2 exclusively, which enables self‐sorting syngas formation at flexible CO/H2 ratios.
Radiation‐induced lung injury (RILI) is the major complication of thoracic radiation therapy, and no effective treatment is available. This study explored the role of high‐mobility group box 1 ...(HMGB1) in acute RILI and the therapeutic effect of glycyrrhizin, an inhibitor of HMGB1, on RILI. C57BL/6 mice received a 20 Gy dose of X‐ray radiation to the whole thorax with or without administration of glycyrrhizin. Severe lung inflammation was present 12 weeks after irradiation, although only a mild change was noted at 2 weeks and could be alleviated by administration of glycyrrhizin. Glycyrrhizin decreased the plasma concentrations of HMGB1 and sRAGE as well as TNF‐α, IL‐1β and IL‐6 levels in the bronchoalveolar lavage fluid (BALF). The expression of RAGE was decreased while that of TLR4 was significantly increased at 12 weeks, but not 2 weeks, after irradiation in mouse lung tissue. In vitro, the expression of TLR4 increased in RAW 264.7 cells after conditioning with the supernatant from the irradiated MLE‐12 cells containing HMGB1 but showed no change when conditioned medium without HMGB1 was used. However, conditioned culture had no effect on RAGE expression in RAW 264.7 cells. Glycyrrhizin also inhibited the related downstream transcription factors of HMGB/TLR4, such as NF‐κB, JNK and ERK1/2, in lung tissue and RAW 264.7 cells when TLR4 was activated. In conclusion, the HMGB1/TLR4 pathway mediates RILI and can be mitigated by glycyrrhizin.
In this study, we attempted to assess the efficacy of upfront brain radiotherapy (RT) in breast cancer (BC) patients with brain metastases (BM). Medical records of 111 consecutive BC patients treated ...with WBRT or SRS between August 2009 and November 2017 in single center were retrospectively reviewed. Eighty patients received upfront brain RT after BM diagnosis and 31 had delayed RT. The median age at BM was 54 years (22‐77), with median KPS 80 (50‐90). The molecular BC subtypes of Luminal A, Luminal B, triple‐negative and HER2 overexpression were 16, 47, 27, and 19, respectively, with 2 unknown. Of them, 83 received WBRT after BM and 28 SRS. Median overall survival (OS) was significantly related to Breast‐GPA, as following: 6.5, 9.9, 14.4, and 24.5 months in 0‐1.0, 1.5‐2.0, 2.5‐3.0, and 3.5‐4.0 subgroups, respectively (P = 0.007). Univariate and multivariate analysis showed that KPS ≤70, infratentorial involvement, extracranial metastases, and no continuing systemic therapy were independent risk factors for OS. In the whole group, no significant difference in OS was found between upfront or delayed RT. For Breast‐GPA 0‐2.0 subgroup, upfront RT was associated with increased median OS (3.3 vs 9.8 months, P = 0.04). In GPA 2.5‐4.0 subgroup, the median OS for upfront and delayed RT was 13.8 and 16.5 months, respectively (P = 0.58). In conclusion, BCBM patients with better KPS, systemic therapy, without infratentorial involvement and extracranial metastases are associated with better OS. Patients with Breast‐GPA 0‐2.0 might benefit from upfront brain RT.
Parent amido complexes are crucial intermediates in ammonia-based transformations. We report a well-defined ferric ammine system Cp*Fe(1,2-Ph2PC6H4NH)(NH3)+ (1-NH3 + ), which processes ...electrocatalytic ammonia oxidation to N2 and H2 at a mild potential. Through establishing elementary e–/H+ conversions with the ferric ammine, a formal Fe(IV)-amido species, 1-NH2 + , together with its conjugated Lewis acid, 1-NH32+ , was isolated and structurally characterized for the first time. Mechanism studies indicated that further oxidation of 1-NH2 + induces the reaction of the parent amido unit with NH3. The formation of hydrazine is realized by the non-innocent nature of the phenylamido ligand that facilitates the concerted transfer of one proton and two electrons.
Purpose
The aim of this study was to evaluate the impact of time to radiotherapy (TTR) after completion of chemotherapy (CT), and TTR after surgery, in breast cancer (BC) patients.
Patients and ...Methods
Continuous breast cancer patients treated with surgery and CT followed by radiotherapy (RT) from 2009 through 2015 were retrospectively reviewed. Patients were categorized into four groups with respect to TTR after CT, i.e. <4, 4–8, 8–12, and >12 weeks, and TTR after surgery, i.e. <147, 147–180, 180–202, and >202 days. The Cox proportional hazards model was used to identify the independent effect of TTRs.
Results
Overall, 989 patients were enrolled. Patients with a TTR of >12 weeks after CT showed significantly worse breast cancer-specific survival (BCSS) and overall survival (OS) compared with those who had a TTR of <4 weeks (BCSS: hazard ratio HR 0.28, 95% confidence interval CI 0.1–0.76; OS: HR 0.33, 95% CI 0.13–0.88), 4–8 weeks (BCSS: HR 0.23, 95% CI 0.08–0.66; OS: HR 0.29, 95% CI 0.11–0.8), and 8–12 weeks (BCSS: HR 0.22, 95% CI 0.05–0.96; OS: HR 0.23, 95% CI 0.06–0.99). TTR after surgery showed no significant association with survival outcomes in the entire cohort, except in patients with hormone receptor (HR)-positive disease and those receiving mastectomy. In HR-positive tumors, a TTR after CT of >12 weeks remained an independent predictor for adverse BCSS and OS.
Conclusion
Initiation of RT beyond 12 weeks after CT might compromise survival outcomes. Efforts should be made to avoid delaying RT, especially after completion of CT and in patients with HR-positive tumors, positive lymph nodes, and those receiving mastectomy.
Doxorubicin (DOX), one useful chemotherapeutic agent, is limited in clinical use because of its serious cardiotoxicity. Growing evidence suggests that angiotensin receptor blockers (ARBs) have ...cardioprotective effects in DOX‐induced cardiomyopathy. However, the detailed mechanisms underlying the action of ARBs on the prevention of DOX‐induced cardiomyocyte cell death have yet to be investigated. Our results showed that angiotensin II receptor type I (AT1R) plays a critical role in DOX‐induced cardiomyocyte apoptosis. We found that MAPK signaling pathways, especially ERK1/2, participated in modulating AT1R gene expression through DOX‐induced mitochondrial ROS release. These results showed that several potential heat shock binding elements (HSE), which can be recognized by heat shock factors (HSFs), located at the AT1R promoter region. HSF2 markedly translocated from the cytoplasm to the nucleus when cardiomyocytes were damaged by DOX. Furthermore, the DNA binding activity of HSF2 was enhanced by DOX via deSUMOylation. Overexpression of HSF2 enhanced DOX‐induced cardiomyocyte cell death as well. Taken together, we found that DOX induced mitochondrial ROS release to activate ERK‐mediated HSF2 nuclear translocation and AT1R upregulation causing DOX‐damaged heart failure in vitro and in vivo.
DOX induces mitochondrial ROS accumulation to activate ERK activation for HSF2‐mediated AT1R upregulation.
Herein, electrochemically driven, Rh(
iii
)-catalyzed regioselective annulations of arenes with alkynes have been established. The strategy, combining the use of a rhodium catalyst with electricity, ...not only avoids the need for using a stoichiometric amount of external oxidant, but also ensures that the transformations proceed under mild and green conditions, which enable broad functional group compatibility with a variety of substrates, including drugs and pharmaceutical motifs. Moreover, the electrolysis reaction was made operationally simple by employing an undivided cell, and proceeds efficiently in aqueous solution in air.
Herein, electrochemically driven, Rh(
iii
)-catalyzed regioselective annulations of arenes with alkynes have been established.
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