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Background: Crizotinib is a tyrosine kinase inhibitor (TKI) effective in ALK/ROS-1/c-MET positive non-small cell lung cancer (NSCLC) patients. Bevacizumab is an antiangiogenic monoclonal antibody, and improves clinical benefit of NSCLC in combination with EGFR-TKIs or chemotherapy. However, the efficacy and safety of crizotinib plus bevacizumab in treating naive ALK/ROS-1/c-MET positive NSCLC patients have not been studied. Methods: In this open-label, single-arm, prospective observational study, locally advanced or metastatic ALK rearrangement/ROS-1 fusion/c-MET amplification NSCLC patients were treated with crizotinib (250 mg orally twice daily) and bevacizumab (7.5 mg/kg intravenous every three weeks) until disease progression or intolerant toxicity or death. Primary end point was progressive free survival (PFS), secondary end points were duration of response (DOR), overall response rate (ORR), disease control rate (DCR) and safety. Patients receiving ≥1 cycle of treatment were evaluated. Findings: Fourteen patients were eligible for analyzing between June 2016 and October 2017. There were 12 patients with ALK rearrangement, 1 patient with ROS-1 fusion, and 1 patient with c-MET amplification. The median follow-up time was 42.8 months. The median PFS and DOR of the patients with ALK rearrangement were 13.9 and 14.8 months respectively. Of the 12 patients, 7 gained partial response, 5 gained stable disease. The ORR and DCR were 58.3% and 100%. The PFS were 12.9 months and 1.9 months for patient with ROS-1 fusion or c-MET amplification. The most two common treatment-related adverse events were fatigue (28.6%) and rash (21.4%). 3 patients discontinued therapy because of liver damage or hemoptysis. Interpretation: This study demonstrated that crizotinib plus bevacizumab showed benefit in treating naive ALK rearrangement NSCLC patients, and the toxicity was relatively tolerant. Our results suggested that crizotinib plus bevacizumab might be a promising treatment strategy in ALK/ROS-1/c-MET positive NSCLC patients.

Due to bioflavonoids non-stabilized in air alkaline solution, the general synthetic procedure for synthesis of bioflavonoids metal complexes in air alkaline solution was considered to be doubtful. In this study, dihydromyricetin (DHM) acting as a representative example of bioflavonoids was selected to make a complexation with varied transition metal ions in air alkaline solution to form DHM metal(II) complexes, as following the general synthetic procedure of bioflavonoids metal complexes. After characterized well by some technologies, their metal complexes were authorized to be hydrolyzed for observing stabilization of DHM of DHM-M(II) complexes under acidic conditions, via HPLC. Subsequently, some of synthetic factors, e.g., metal ion, alkalinity and refluxing time were solely and respectively investigated by UV-Vis spectrophotometer or HPLC in affecting dihydromyricetin stabilization. Finally, by means of EPR spectroscopy, dihydromyricetin and its analogues were observed with the help of DMPO (5,5-dimethyl-1-pyrroline-N-oxide) capable to form a relatively stable free radical adduct in air alkaline solution. As a result, the results demonstrated that dihydromyricetin metal(II) complexes after undergoing hydrolysis in acidic solution is proved not to be a single content of DHM in LC spectra by HPLC, indicating that partial dihydromyricetin could make a reaction in the process of synthesizing dihydromyricetin metal(II) complexes. Simultaneously, both of transition metal ion and alkalinity were testified to be predominant synthetic factors of dihydromyricetin metal(II) complexes, because of free dihydromyricetin stabilization affected seriously. Furthermore, dihydromyricetin and its analogues were witnessed to be generators of superoxide-anion radical in air alkaline solution, with observing typical signals of DMPO-OO·- adduct by EPR. And their capacities of generating superoxide anion were close to numbers and/ or locations of hydroxyl groups attached to molecule skeleton or their configurations. Interestingly, dihydromyricetin reacted with superoxide anion can be transformed into myricetin, which is involving in a C3 H atom of DHM abstracted by O2.- in mechanism. Therefore, the general synthetic procedure for synthesis of bioflavonoids metal complexes in air alkaline solution should be unreasonable.

The three-component Mannich reaction of among dimethyl malonate, aromatic primary amine, and aromatic aldehyde was made successfully in the presence of solid acidic catalyst SO42−/TiO2, with excellent catalytic activity, as compared to SO42−/γ-Al2O3 and SO42−/ZnO. To the best of our knowledge, SO42−/TiO2 prepared at varied calcination temperatures can perform different intensities of Lewis and Bronsted acidities. Because of this point, under the optimum conditions, the effect of SO42−/TiO2 (prepared at 200°C) was much more than that of SO42−/TiO2 (prepared at 300°C or 400°C) in the three-component Mannich reaction. In observing ionization activation mode of the three-component Mannich reaction, it disclosed that the plausible mechanism possibly undergoes formation of aldimines and transformation of aldimines into β-amino esters by applying solid acidic catalyst SO42−/MxOy.

Two novel chiral Br?nsted acids 3b and 3c were prepared without involving the complexity of Suzuki coupling. Catalyst 3c bearing two additional hydroxyl groups at 3 and 3′ positions of axially chiral 1,1-binaphthalene-2,2′-diol phosphoric acid was applied in a model Mannich reaction to afford β-amino ester in high yield (92%) and enantiomeric excess (91%) at low reacting temperature of −40°C. In addition, those β-amino ester derivatives with high yields and excellent enatioselectivities were obtained in the presence of catalyst 3c under the above condition.

β-Amino esters (III) are synthesized with high yields and excellent enantioselectivities via Mannich reaction using an axially chiral (R)-1,1-binaphthalene-2,2′-diol phosphoric acid catalyst.