Synthesis of Chiral Diarylmethylamides via Catalytic Asymmetric Aza-Michael Addition of Amides to ortho-Quinomethanes.

Chiral diarylmethylamides are a privileged skeleton in many bioactive molecules. However, the enantioselective synthesis of such molecules remains a long-standing challenge in organic synthesis. Herein, we report a chiral bifunctional squaramide catalyzed asymmetric aza-Michael addition of amides to in situ generated ortho-quinomethanes, affording enantioenriched diarylmethylamides in good yields with excellent enantioselectivities. This work not only provides a new strategy for the construction of the diarylmethylamides but also represents the practicability of amides as nitrogen-nucleophiles in asymmetric organocatalysis.

Diastereo- and Enantioselective Synthesis of Eight-Membered N-Heterocycles from Benzofuran-Derived Azadienes and Ynones.

Enantioselective synthesis of eight-membered N-heterocycles represents a long-standing challenge in organic synthesis. Here, by combining the squaramide and DBU catalysis, a sequential asymmetric conjugate addition/cyclization reaction between benzofuran-derived azadienes and ynones has been well-developed, providing straightforward access to chiral eight-membered N-heterocycles in high yields with stereoselectivities. This protocol features the use of a bifunctional squaramide catalyst for controlling the enantioselectivity of products, while the DBU is utilized to achieve intramolecular cyclization and improve the diastereoselectivity of products.

Cost-effectiveness analysis of continuing bevacizumab plus chemotherapy versus chemotherapy alone after first progression of metastatic colorectal cancer.

BACKGROUND: Continuation of bevacizumab plus second-line chemotherapy has significantly improved overall and progression-free survival in patients with metastatic colorectal cancer (mCRC). However, the cost-effectiveness of such high cost therapy is still uncertain in China; so this analysis was performed to evaluate the cost-effectiveness of these treatment options from the Chinese health care system perspective. METHODS: A cost-effectiveness analysis was conducted using data from the ML18147 trial (ClinicalTrials.gov identifier NCT00700102) by modeling a partitioned survival model. Main evaluation indicators were quality-adjusted life years (QALYs) and incremental cost-effectiveness ratio (ICER) with a willingness to pay (WTP) threshold of $38,201 per QALY. One-way and probabilistic sensitivity analyses were conducted to assess the robustness and stability of the model. Subgroup and scenario analyses were also performed to make our study more relevant. RESULTS: Bevacizumab plus chemotherapy increased 0.12 QALYs and an incremental cost of $22,761.62 compared with chemotherapy, resulting in an ICER of $188,904.09 per QALY. The model was most sensitive to the utility of progression-free survival and the cost of bevacizumab. Compared with chemotherapy, bevacizumab plus chemotherapy had a 0% cost-effectiveness probability, and no cost-effectiveness in subgroups at the WTP threshold of $38,201 per QALY. The scenario analysis found that bevacizumab biosimilar gained an ICER of $126,397.38 per QALY when assuming the cost of drugs was calculated at the most affordable price. CONCLUSIONS: At the WTP threshold of $38,201 per QALY, continuation of bevacizumab plus chemotherapy is unlikely considered cost-effective for patients after first progression of mCRC.

Cost-effectiveness analysis of selexipag for the combined treatment of pulmonary arterial hypertension.

Objective: Adding selexipag to the combined treatment of endothelin receptor antagonists (ERA) and phosphodiesterase 5 inhibitor (PDE5i) reduces the risk of clinical worsening events in patients with pulmonary arterial hypertension (PAH) but at a considerably higher cost. This study evaluated the cost-effectiveness of adding selexipag to the combined treatment of ERA and PDE5i in patients with PAH from a Chinese healthcare system perspective. Methods: A Markov model was developed to assess costs and quality-adjusted life years (QALYs) of macitentan + tadalafil + selexipag vs. macitentan + tadalafil for the treatment of PAH. Markov states included WHO Functional Class (FC) (I-IV) and death. Transition probabilities were based on data from the TRITON trial. Mortality rates, costs, and utilities were obtained from published literature and public databases. Results: In the base case analysis, compared with macitentan + tadalafil, selexipag + macitentan + tadalafil increased costs ($357,807.588 vs. $116,534.543, respectively) and QALYs (7.234 QALYs vs. 6.666 QALYs, respectively). The resulting incremental cost-effectiveness ratio was $424,746.070 per QALY, which was higher than the willingness-to-pay (WTP) of $38,223.339 per QALY. The results were most sensitive to HR for mortality of patients with FC IV relative to the general population, discount rate, and the cost of selexipag. The probability was greater than 50% for the selexipag + macitentan + tadalafil only if the WTP was more significant than $426,019.200 per QALY. Conclusion: In China, adding selexipag may not be cost-effective for patients with PAH who failed to control their condition after combined treatment of ERA and PDE5i. Results of the analysis can aid discussions on the value and position of selexipag for the combined treatment of PAH.

Metal-free and enantioselective synthesis of 1,4-benzoxazepines from para-quinone methide derivatives and α-bromohydroxamates.

A sequential asymmetric conjugate addition/cyclisation of α-bromohydroxamates with para-quinone methide derivatives has been developed, which provides enantioenriched 1,4-benzoxazepines in generally high yields (up to 95%) and good enantioselectivities (up to 97 : 3 er). This protocol not only offers a novel and straightforward strategy for constructing chiral 1,4-benzoxazepines, but also demonstrates the potential of α-bromohydroxamates as three-atom synthons in asymmetric cyclisation reactions.

Visible light-induced oxidative α-hydroxylation of ß-dicarbonyl compounds catalyzed by ethylenediamine-copper(ii).

We have developed an efficient oxidative α-hydroxylation of ß-keto esters with firstly using the structurally simple ethylenediamine-copper(ii) as a catalyst for ß-keto esters activation and using visible light as the driving force for generating more active singlet oxygen (1O2) from triplet state oxygen (3O2) in the air, providing a series of α-hydroxy ß-keto esters in excellent yields (up to 99%) under extremely low photosensitizer loading (0.01 mol%) and catalyst loading (1 mol%) within a short time. Moreover, the gram-scale synthesis showed the practical utility of this protocol.

Copper-catalyzed asymmetric 1,6-conjugate addition of in situ generated para-quinone methides with ß-ketoesters.

A Cu-catalyzed asymmetric 1,6-conjugate addition of in situ generated para-quinone methides (p-QMs) with ß-ketoester has been developed to construct a ketoester skeleton bearing an adjacent tertiary-quaternary carbon stereocenter in good yields and high enantioselectivities. This is the first example of metal-catalyzed asymmetric transformations of the in situ generated p-QMs, avoiding using pre-synthesized p-QMs requiring bulky 2,6-substitutions and highlighting a new dual catalytic activation with the chiral bis(oxazoline)-metal complex acting as a normal Lewis acid to activate the ß-ketoesters and a source of Brønsted acid responsible for generating the p-QMs in situ.

Asymmetric bis(oxazoline)-Ni(II) catalyzed α-hydroxylation of cyclic ß-keto esters under visible light.

Using visible light as a driving force and molecular oxygen as a green oxidant, we developed bis(oxazoline)-Ni(acac)2 catalyzed asymmetric α-hydroxylation of ß-keto esters under low photosensitizer loading, and the protocol enabled an efficient transformation to provide the desired chiral α-hydroxy-ß-keto esters in high yields (up to 99%) and enantioselectivities (up to 99% ee) at room temperature.

Regio- and Enantioselective Friedel-Crafts Benzhydrylation of Indoles in Carbocyclic Ring with ortho-Quinomethanes: Access to Chiral Diarylindolylmethanes.

The functionalization of indoles in the carbocyclic ring has been achieved via organocatalytic enantioselective Friedel-Crafts benzhydrylation of hydroxyindoles with in situ generated ortho-quinomethanes in oil-water biphases, allowing an efficient access to varied diarylindolylmethanes with a wide substrate scope. The high yields, excellent stereoselectivities, mild conditions, low catalyst loading, and easy scalability also demonstrated the interest of this novel methodology.

Asymmetric copper-catalyzed fluorination of cyclic ß-keto esters in a continuous-flow microreactor.

A highly enantioselective homogeneous fluorination of cyclic ß-keto esters catalyzed by diphenylamine linked bis(oxazoline)-Cu(OTf)2 complexes has been established in a continuous flow microreactor. The microreactor allowed an efficient transformation with reaction times ranging from 0.5 to 20 min, and the desired products were afforded in high yields (up to 99%) with excellent enantioselectivities (up to 99% ee) at a low catalyst loading of 1 mol%.

Pharmacokinetic-Based Drug-Drug Interactions with Anaplastic Lymphoma Kinase Inhibitors: A Review.

Anaplastic lymphoma kinase (ALK) inhibitors are important treatment options for non-small-cell lung cancer (NSCLC), associated with ALK gene rearrangement. Patients with ALK gene rearrangement show sensitivity to and benefit clinically from treatment with ALK tyrosine kinase inhibitors (ALK-TKIs). To date, crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, and entrectinib have received approval from the US Food and Drug Administration and/or the European Medicines Agency for use during the treatment of ALK-gene-rearrangement forms of NSCLC. Although the oral route of administration is convenient and results in good compliance among patients, oral administration can be affected by many factors, such as food, intragastric pH, cytochrome P450 enzymes, transporters, and p-glycoprotein. These factors can result in increased risks for serious adverse events or can lead to reduced therapeutic effects of ALK-TKIs. This review characterizes and summarizes the pharmacokinetic parameters and drug--drug interactions associated with ALK-TKIs to provide specific recommendations for oncologists and clinical pharmacists when prescribing ALK-TKIs.

Regioselective catalytic asymmetric N-alkylation of isoxazol-5-ones with para-quinone methides.

A highly regioselective and enantioselective N-alkylation of isoxazol-5-ones with para-quinone methides promoted by bi-functional squaramide catalysts was developed. This unexpected asymmetric N-addition of isoxazolinones afforded a series of enantioenriched N-diarylmethane substituted isoxazolinones with high yields and enantioselectivities (up to 97 : 3 er). This reaction not only provides a useful approach for intermolecular chiral C-N bond formation but also demonstrates the immense potential of isoxazol-5-ones as N-nucleophiles in catalytic asymmetric reactions.

Prolonged low-dose infusion for gemcitabine: a systematic review.

BACKGROUND: The present standard dose of gemcitabine (Gem), a pyrimidine antimetabolite, is 1,000-1,250 mg/m2, and the infusion time is 30 min. However, pharmacological studies have demonstrated that Gem with prolonged infusion could attain a better accumulation rate of Gem triphosphate (active metabolites of Gem), indicating that Gem with prolonged infusion is superior to 30-min infusion. Thus, this systematic review aims to provide some references for Gem administered as a prolonged infusion. METHODS: We searched electronic databases, including PubMed, EMBASE, Cochrane Library, and CNKI, for trials. Keywords were "Gem," "prolonged infusion," and "low-dose." In addition, we used the Cochrane Handbook V5.1.0 and methodological index for non-randomized studies to evaluate the quality of randomized controlled trials (RCTs) and non-RCTs, respectively. Furthermore, Cochrane Collaboration guidelines and the PRISMA statement were adopted. RESULTS: We systematically reviewed 19 studies (5 RCTs and 14 non-RCTs). All studies assessed the efficacy and safety of Gem administered as a prolonged low-dose infusion (P-LDI) and reported that Gem administered as P-LDI was effective and well tolerated. CONCLUSION: Gem administered as P-LDI is effective, safe, and economical, especially suited for patients with poor performance status or without good economic condition.

Asymmetric fluorination of indanone-2-carboxylates using a polystyrene-supported diphenylamine-linked bis(oxazoline) complex.

A highly enantioselective fluorination of indanone-2-carboxylates catalyzed by a polystyrene-supported diphenylamine-linked bis(oxazoline) (PS-box)-Cu(OTf)2 complex has been developed in a continuous flow system. The supported complex exhibited extremely efficient catalytic performance with high activity, affording the corresponding products in excellent yields (up to 99% yield) with excellent enantioselectivities (up to 99% ee) and more than 4000 turnover number (TON).

Asymmetric conjugate additions of 2-substituted benzofuran-3(2H)-ones to α,ß-unsaturated ketones catalyzed by chiral copper complexes.

A highly enantioselective conjugate addition of 2-substituted benzofuran-3(2H)-ones to α,ß-unsaturated ketones promoted by chiral copper complexes has been developed, affording the Michael addition products with quaternary stereocenters in good to high yields (up to 95% yield) with excellent enantioselectivities (up to 99% ee). The chiral Michael adducts could be readily converted to the polycyclic benzofuran-type framework via the Robinson annulation.

Structure effect on graphene-modified enzyme electrode glucose sensors.

Using structural characterizations and electrochemical measurements, we explored and investigated the effect of the structure of enzyme electrodes with glucose oxidase (GOD) that were modified by reduced graphene oxide (rGO) sheets. The rGO sheets with different defect density, layers, and oxygen concentrations were chosen to modify the enzyme electrode, and all the modified enzyme electrodes exhibited excellent electrocatalytic activities and performances towards glucose. The abundant defects in rGO induce easy absorption of GOD. At a low oxygen concentration, rGO sheets help to induce the direct electron transfer (DET) on the rGO-modified electrode, and at a higher oxygen concentration, the reduction of H2O2 occurred instead of DET on the surface of the rGO-modified electrode. When rGO modified the enzyme electrode under the working model of H2O2 reduction, an increase in the number of the oxygen functional groups could lead to an increase in the absorption of GOD, resulting in the improvement of the affinity and sensitivity of the biosensor. The rGO-modified enzyme electrode can provide faster response, higher sensitivity, and better affinity by optimizing and controlling the structure of graphene and its derivatives.

Angiogenesis inhibition and cell cycle arrest induced by treatment with Pseudolarix acid B alone or combined with 5-fluorouracil.

Angiogenesis inhibitors combined with chemotherapeutic drugs have significant efficacy in the treatment of a variety of cancers. Pseudolarix acid B (PAB) is a traditional pregnancy-terminating agent, which has previously been shown to reduce tumor growth and angiogenesis. In this study, we used the high content screening assay to examine the effects of PAB on human umbilical vein endothelial cells (HUVECs). Two hepatocarcinoma 22-transplanted mouse models were used to determine PAB efficacy in combination with 5-fluorouracil (5-Fu). Our results suggested that PAB (0.156-1.250 µM) inhibited HUVECs motility in a concentration-dependent manner without obvious cytotoxicity in vitro. In vivo, PAB (25 mg/kg/day) promoted the anti-tumor efficacy of 5-Fu (5 mg/kg/2 days) in combination therapy, resulting in significantly higher tumor inhibition rates, lower microvessel density values, and prolonged survival times. It was also demonstrated that PAB acted by blocking the cell cycle at both the G(1)/S boundary and M phase, down-regulation of vascular endothelial growth factor, hypoxia-inducible factor 1α and cyclin E expression, and up-regulation of cdc2 expression. These observations provide the first evidence that PAB in combination with 5-Fu may be useful in cancer treatment.

Development of ELISA for metallothionein-II allows determination of heavy metal pollution of fresh water.

Metallothionein (MT), a metal-binding protein induced primarily by heavy metals in vertebrates, is considered a biomarker for environmental heavy-metal contamination. To investigate heavy metal pollution in the freshwater environment, MT-I and MT-II were purified from livers of crucian carp (Carassius carassius) by gel exclusion chromatography and ion exchange chromatography. To detect the purified MT-II, a specific monoclonal antibody (mAb) against crucian carp MT-II was produced from the hybridoma strains by cell-cell fusion. By using Enzyme-Linked Immunosorbent Assay (ELISA) with this mAb, the purified crucian carp MT-II was detected with a high specificity and sensitivity. There was a good correlation between the amount of MT-II in carp livers and the concentration of heavy metals in water. ELISA was then used to evaluated the degree of heavy metal pollution in two freshwater systems. The results indicate that the MT-II content in carp liver tissue can be used as an indicator of environmental heavy-metal pollution.

Cloning of crucian carp (Carassius cuvieri) metallothionein-II gene and characterization of its gene promoter region.

The genomic DNA of crucian carp (Carassius cuvieri) metallothionein-II (ccMT-II), with its upstream region, was obtained. The sequence analysis of its upstream region revealed several putative cis-acting elements including seven metal regulatory elements (MREs), three activator protein 1 (AP1), two glucocorticoid response elements (GREs), etc. The seven MREs locate into two clusters, a distal cluster with four MREs within -800/-600bp from the translation start site and a proximal cluster with three MREs close to TATA box. In transient luciferase gene expression assays, both of the distal and proximal cluster MREs have significantly shown synergistic effects in the transcription of ccMT-II gene; the proximal cluster of MREs serves as the major elements in metal inducing activity; Zn(2+) and Cd(2+) served as much stronger inducers than Cu(2+) shown in ccMT-II expression. The two GRE homologous sequences in ccMT-II promoter showed not to be inductive in either HepG2 or HEK293.