Relatively low reactivity hinders using chlorodifluoromethane (ClCF
H) for general difluoromethylation with organic molecules, despite its availability as an inexpensive industrial chemical. To date, ...transformations of ClCF
H are very limited and most of them involve difluorocarbene intermediate. Here, we describe a strategy for difluoromethylation of aromatics through nickel-catalyzed cross-coupling of ClCF
H with readily accessible (hetero)aryl chlorides. The reaction proceeds under mild reaction conditions with high efficiency and features synthetic simplicity without preformation of arylmetals and broad substrate scope, including a variety of heteroaromatics and commercially available pharmaceuticals. The reliable practicability and scalability of the current nickel-catalyzed process has also been demonstrated by several 10-g scale reactions without loss of reaction efficiency. Preliminary mechanistic studies reveal that the reaction starts from the oxidative addition of aryl chlorides to Ni(0) and a difluoromethyl radical is involved in the reaction, providing a route for applications of ClCF
H in organic synthesis and related chemistry.
Summary Background The value of adding cisplatin, fluorouracil, and docetaxel (TPF) induction chemotherapy to concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma is ...unclear. We aimed to compare TPF induction chemotherapy plus concurrent chemoradiotherapy with concurrent chemoradiotherapy alone in a suitably powered trial. Methods We did an open-label, phase 3, multicentre, randomised controlled trial at ten institutions in China. Patients with previously untreated, stage III–IVB (except T3-4N0) nasopharyngeal carcinoma, aged 18–59 years without severe comorbidities were enrolled. Eligible patients were randomly assigned (1:1) to receive induction chemotherapy plus concurrent chemoradiotherapy or concurrent chemoradiotherapy alone (three cycles of 100 mg/m2 cisplatin every 3 weeks, concurrently with intensity-modulated radiotherapy). Induction chemotherapy was three cycles of intravenous docetaxel (60 mg/m2 on day 1), intravenous cisplatin (60 mg/m2 on day 1), and continuous intravenous fluorouracil (600 mg/m2 per day from day 1 to day 5) every 3 weeks before concurrent chemoradiotherapy. Randomisation was by a computer-generated random number code with a block size of four, stratified by treatment centre and disease stage (III or IV). Treatment allocation was not masked. The primary endpoint was failure-free survival calculated from randomisation to locoregional failure, distant failure, or death from any cause; required sample size was 476 patients (238 per group). We did efficacy analyses in our intention-to-treat population. The follow-up is ongoing; in this report, we present the 3-year survival results and acute toxic effects. This trial is registered with ClinicalTrials.gov , number NCT01245959. Findings Between March 1, 2011, and Aug 22, 2013, 241 patients were assigned to induction chemotherapy plus concurrent chemoradiotherapy and 239 to concurrent chemoradiotherapy alone. After a median follow-up of 45 months (IQR 38–49), 3-year failure-free survival was 80% (95% CI 75–85) in the induction chemotherapy plus concurrent chemoradiotherapy group and 72% (66–78) in the concurrent chemoradiotherapy alone group (hazard ratio 0·68, 95% CI 0·48–0·97; p=0·034). The most common grade 3 or 4 adverse events during treatment in the 239 patients in the induction chemotherapy plus concurrent chemoradiotherapy group versus the 238 patients in concurrent chemoradiotherapy alone group were neutropenia (101 42% vs 17 7%), leucopenia (98 41% vs 41 17%), and stomatitis (98 41% vs 84 35%). Interpretation Addition of TPF induction chemotherapy to concurrent chemoradiotherapy significantly improved failure-free survival in locoregionally advanced nasopharyngeal carcinoma with acceptable toxicity. Long-term follow-up is required to determine long-term efficacy and toxicities. Funding Shenzhen Main Luck Pharmaceuticals Inc, Sun Yat-sen University Clinical Research 5010 Program (2007037), National Science and Technology Pillar Program during the Twelfth Five-year Plan Period (2014BAI09B10), Health & Medical Collaborative Innovation Project of Guangzhou City (201400000001), Planned Science and Technology Project of Guangdong Province (2013B020400004), and The National Key Research and Development Program of China (2016YFC0902000).
The extraction behavior of thorium from Baotou iron ore with primary amine N1923 levextrel resins by a micro-column was investigated under the decompression technology. Thorium was adsorbed on the ...micro-column conditioned by 3 mol L
−1
HCl solution before use. The washing liquor of 0.5 mol L
−1
H
2
SO
4
–0.1 mol L
−1
H
3
PO
4
solution was used to wash impurity elements and the solution of 3 mol L
−1
HCl was used as the eluent for thorium. The method was applied to analyze thorium in the Baotou iron ore sample. The relative standard deviations of thorium in R-715 standard sample, Baotou main ore standard sample and Baotou west ore were of 0.49%, 1.63%, 1.16%, respectively. The accuracy of the method was satisfactory.
To report long‐term results of a randomized controlled trial that compared cisplatin/fluorouracil/docetaxel (TPF) induction chemotherapy (IC) plus concurrent chemoradiotherapy (CCRT) with CCRT alone ...in locoregionally advanced nasopharyngeal carcinoma (NPC). Patients with stage III–IVB (except T3–4 N0) NPC were randomly assigned to receive IC plus CCRT (n = 241) or CCRT alone (n = 239). IC included three cycles of docetaxel (60 mg/m2 d1), cisplatin (60 mg/m2 d1), and fluorouracil (600 mg/m2/d civ d1–5) every 3 weeks. Patients from both groups received intensity‐modulated radiotherapy concurrently with three cycles of 100 mg/m2 cisplatin every 3 weeks. After a median follow‐up of 71.5 months, the IC plus CCRT group showed significantly better 5‐year failure‐free survival (FFS, 77.4% vs. 66.4%, p = 0.019), overall survival (OS, 85.6% vs. 77.7%, p = 0.042), distant failure‐free survival (88% vs. 79.8%, p = 0.030), and locoregional failure‐free survival (90.7% vs. 83.8%, p = 0.044) compared to the CCRT alone group. Post hoc subgroup analyses revealed that beneficial effects on FFS were primarily observed in patients with N1, stage IVA, pretreatment lactate dehydrogenase ≥170 U/l, or pretreatment plasma Epstein–Barr virus DNA ≥6000 copies/mL. Two nomograms were further developed to predict the potential FFS and OS benefit of TPF IC. The incidence of grade 3 or 4 late toxicities was 8.8% (21/239) in the IC plus CCRT group and 9.2% (22/238) in the CCRT alone group. Long‐term follow‐up confirmed that TPF IC plus CCRT significantly improved survival in locoregionally advanced NPC with no marked increase in late toxicities and could be an option of treatment for these patients.
What's new?
Despite advances in the treatment of nasopharyngeal carcinoma, approximately 30% of high‐risk patients experience recurrence after treatment. Here the authors find that combining the conventional chemoradiotherapy with a triple induction chemotherapy (cisplatin/fluorouracil/docetaxel) prolonged survival of patients with locoregionally advanced cancer, even after more than 70 months of follow‐up. The combination treatment increased acute, but not late, toxicities, and the authors propose that it could present a new treatment option for this patient group.
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are being wildly used as target therapy in non-small-cell lung cancer (NSCLC). However, NSCLC patients with wild-type EGFR ...and KRAS mutation are primary resistant to EGFR-TKIs such as gefitinib. Curcumin has been known as a potential therapeutic agent for several major human cancers. In this study, we investigated the effect of curcumin on the reversal of gefitinib resistance in NSCLC cells as well as their molecular bases.
H157 (wild-type EGFR and KARS mutation) and H1299 (wild-type EGFR and HRAS mutation) cells were treated with gefitinib or curcumin alone, or the two combination, and then cell viability, EGFR activity, expressions of Sp1 and Sp1-dependent proteins and receptor tyrosine kinases, markers of autophagy and apoptosis were examined by using CCK-8, colony formation, immunoblot, quantitative PCR, immunofluoscence, and flow cytometry assays. Also xenograft experiments were conduced to test the synergism of curcumin to gefitinib.
Our results showed that curcumin significantly enhanced inhibitory effect of gefitinib on primary gefitinib-resistant NSCLC cell lines H157 and H1299. Combination treatment with curcumin and gefitinib markedly downregulated EGFR activity through suppressing Sp1 and blocking interaction of Sp1 and HADC1, and markedly suppressed receptor tyrosine kinases as well as ERK/MEK and AKT/S6K pathways in the resistant NSCLC cells. Meanwhile, combination treatment of curcumin and gefitinib caused dramatic autophagy induction, autophagic cell death and autophagy-mediated apoptosis, compared to curcumin or gefitinib treatment alone, as evidenced by the findings that curcumin and gefitinib combination treatment-produced synergistic growth inhibition and apoptosis activation can be reversed by pharmacological autophagy inhibitors (Baf A1 or 3-MA) or knockdown of Beclin-1 or ATG7, also can be partially returned by pan-caspase inhibitor (Z-VAD-FMK) in H157 and H1299 cells. Xenograft experiments in vivo yielded similar results.
These data indicate that the synergism of curcumin on gefitinib was autophagy dependent. Curcumin can be used as a sensitizer to enhance the efficacy of EGFR-TKIs and overcome the EGFR-TKI resistance in NSCLC patients with wild-type EGFR and/or KRAS mutation.
A stereodivergent synthesis of tetrahydrofuroindoles through palladium‐catalyzed asymmetric dearomative formal 3+2 cycloaddition of nitroindoles with epoxybutenes was developed. The polarity of the ...solvent was found to play a key role in the diastereoselectivity. In toluene, good to excellent yields (70–99 %), diastereoselectivity (87/13‐>95/5 d.r.), and enantioselectivity (85/15–94/6 e.r.) were obtained, regardless of the properties of the substituents on nitroindoles. In acetonitrile, tetrahydrofuroindoles of a different diastereoisomer were produced with good to excellent yields (75–98 %) and stereoselectivity (78/22–93/7 d.r., 93/7–99/1 e.r.). Mechanistic studies were conducted to illustrate the origin of the diastereodivergency. The kinetic experiments indicate that the rate‐determining step of this reaction is different in different solvents. ESI‐MS experiments also support the existence of key palladium complex intermediates and the catalytic cycle of the reaction.
Two roads diverged: A stereodivergent synthesis of tetrahydrofuroindoles through palladium‐catalyzed asymmetric dearomative formal 3+2 cycloaddition of nitroindoles with epoxybutenes was developed. The polarity of the solvent was found to play a key role in the diastereoselectivity, with toluene giving one diastereoisomer and acetonitrile giving another.
A palladium‐catalyzed intermolecular dynamic kinetic asymmetric dearomatization of 3‐arylindoles with internal alkynes was developed with the use of achiral Xantphos and chiral sulfinamide phosphine ...ligand (PC‐Phos) as the co‐ligands. This method could deliver various spiroindene‐1,3′‐indole compounds in good yields (up to 95 % yield) with up to 98 % ee. The salient features of the transformation include the use of readily available substrates, ease of scale‐up and the versatile functionalization of the products. The mechanistic experiments gave some insights on active intermediates.
A palladium‐catalyzed intermolecular asymmetric dearomatization of 3‐arylindoles with internal alkynes was developed with the use of achiral Xantphos and chiral sulfinamide phosphine ligand (PC‐Phos) as the co‐ligands. This method could deliver various spiroindene‐1,3′‐indole compounds in good yields (up to 95 % yield) with up to 98 % ee.
Reported is a novel two‐step ring‐expansion strategy for expeditious synthesis of all ring sizes of synthetically challenging (hetero)aryl‐fused medium‐sized lactams from readily available ...5–8‐membered cyclic ketones. This step‐economic approach features a remote radical (hetero)aryl migration from C to N under visible‐light conditions. Broad substrate scope, good functional‐group tolerance, high efficiency, and mild reaction conditions make this procedure very attractive. In addition, this method also provides expedient access to 13–15‐membered macrolactams upon an additional one‐step manipulation. Mechanistic studies indicate that the reaction involves an amidyl radical and is promoted by acid.
Growth rings: A two‐step ring‐expansion strategy for expedient synthesis of all ring sizes of synthetically challenging (hetero)aryl‐fused medium‐sized lactams from readily available 5–8‐membered cyclic ketones has been developed. The key step involves an uncommon remote radical (hetero)aryl migration from C to N by C−C bond cleavage under irradiation with visible light.
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•A cellulose nanofibril based adsorbent with abundant carboxyl/amino was prepared.•After modification by PEI, the Cu adsorption capacity of nanofibril increased.•TOCN-PEI has good ...Cu(II) removal ability and its maximum capacity was 52.32mgg−1.•Results show Cu adsorption on TOCN-PEI is an exothermic and enthalpy-driven process.•Sorption-desorption tests reveal that TOCN-PEI has good stability for Cu removal.
This study describes the preparation of a novel adsorbent based on cellulose nanofibrils by first TEMPO mediated oxidation and then PEI grafting (TOCN-PEI) for heavy metal removal. FTIR results demonstrated the successful introduction of the adsorption functional groups (carboxyl and amino groups), and the elemental analysis and acid base titration were used to quantify the contents of these introduced groups. The kinetics curve suited the pseudo-second-order model better and the equilibrium data well fitted the Langmuir model, with the maximum Cu(II) uptake of 52.32mgg−1. Kinetic study showed that the PEI grafting increased the initial adsorption rate of the TOCN-PEI compared with the adsorbents without PEI. Thermodynamic study was carried out through isothermal titration calorimetry (ITC) measurement and the binding reaction was found to be exothermic and driven by enthalpy change. The adsorption process by TOCN-PEI was pH dependent, and decreasing pH would lead to desorption of Cu(II) ions, thus make the reuse of the absorbent more convenient through adsorption-desorption cycles.
Crystalline porous organic salts (CPOSs), as an emerging class of porous organic materials, combining the uniform microporous system and distinct polarized channels, have become a highly evolving ...field of important current interest. The unique ionic bond of a CPOS endows the confined channels with high polarity, making CPOSs distinct from other organic frameworks. CPOSs show many fascinating properties, such as proton conductivity and fast transport of polar molecules, which involve the interaction between highly polarized guest molecules and host frameworks. Substantial progress has been made in the synthesis and applications of CPOSs. Herein, an overview is provided to impart a comprehensive understanding of the link between the synthetic approaches and the resultant microporous structure, the structure–function correlation and the state‐of‐the‐art applications of CPOSs. The enhanced mass‐transport performance of hierarchically porous structure in combination with the intrinsic polarized channels of CPOSs is very promising to create new applications and contribute to a new research upsurge. The perspective to construct porous hierarchy within the crystalline porous organic salts is assessed and will open a new research avenue. In the conclusion, the current challenges on the synthesis, structural regulation, and applications of CPOSs and the future of hierarchically porous crystalline organic salts are discussed.
An overview of recent achievements in the synthetic approaches, structural features, and state‐of‐the‐art applications of crystalline porous organic salts (CPOSs) and a perspective on the construction of the porous hierarchy within the CPOS frameworks are described.
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