Preparation and in vitro/in vivo evaluation of anastrozole reservoir‐type intravaginal ring

This report details the preparation of anastrozole (ATZ) reservoir‐type intravaginal ring (IVR) and the detection of the concentration of ATZ in beagle dog plasma by liquid chromatography–tandem mass spectrometry (LC–MS/MS). An ATZ reservoir‐type IVR which included ATZ silicone elastomer core and a nonactive silicone layer was manufactured by reaction injection moulding at 80°C for 20 min. An in vitro release experiment was performed under sink conditions and the samples were determined by high‐performance liquid chromatography. A bioanalytical method was developed and validated for determination of ATZ in beagle dog plasma for IVR development. The analytical method consisted of the extraction of plasma samples and determination of ATZ by LC–MS/MS using buspirone as the internal standard. Separation was achieved on a Kinetex‐C₁₈ 110A column (3 × 30 mm, 2.6 μm, Phenomenex) using step‐gradient mobile phase and an isocratic flow rate consisting of formic acid. Protonated ions formed by a turboion spray in the positive mode was used to detect the analyte (ATZ) and internal standard. The MS–MS detection was performed on a triple quadrupole mass spectrometer equipped with electrospray ionization source. The mass spectrometer was operated in the multiple reaction monitoring mode. The mass transition ion‐pair was followed as m/z from 294.10 to 225.08 for anastrozole and m/z from 386.23 to 122.11 for buspirone. The results proved that the correlation between in vitro and in vivo analyses was relatively good.     

Weight enumerators of reducible cyclic codes and their dual codes

Let ${\mathbb{F}}_q$ be a finite field and $n$ a positive integer. In this paper, we find a new combinatorial method to determine weight enumerators of reducible cyclic codes and their dual codes of length $n$ over ${\mathbb{F}}_q$, which just generalize results of Zhu et al. (2015); especially, we also give the weight enumerator of a cyclic code, which is viewed as a partial Melas code. Furthermore, weight enumerators obtained in this paper are all in the form of power of a polynomial.     

镍催化环丁酮肟酯与芳基锌试剂的Negishi偶联反应

发展了一种镍催化环丁酮肟酯和芳基锌试剂之间Negishi偶联的方法.镍既作为亚胺自由基的引发剂,也作为芳基锌试剂与烷基自由基偶联反应的催化剂在反应中起作用.本方法可避免使用剧毒的氰化物,且具有很广的底物适应性和官能团兼容性,因此可能是一种具有潜在吸引力的高效合成烷基腈类化合物的新策略.初步的机理研究显示,该反应极可能经历自由基历程.     

Potent Anticancer Efficacy of First-In-Class CuII and AuIII Metaled Phosphorus Dendrons with Distinct Cell Death Pathways

First-in-class Cu^II and Au^III metaled phosphorus dendrons were synthesized and showed significant antiproliferative activity against several aggressive breast cancer cell lines. The data suggest that the cytotoxicity increases with reducing length of the alkyl chains, whereas the replacement of Cu^II with Au^III considerably increases the antiproliferative activity of metaled phosphorus dendrons. Very interestingly, we found that the cell death pathway is related to the nature of the metal complexed by the plain dendrons. Cu^II metaled dendrons showed a potent caspase-independent cell death pathway, whereas Au^III metaled dendrons displayed a caspase-dependent apoptotic pathway. The complexation of plain dendrons with Au^III increased the cellular lethality versus dendrons with Cu^II and promoted the translocation of Bax into the mitochondria and the release of Cytochrome C (Cyto C).     

Cycloaddition Reactions of an Active Cyclic Phosphane/Borane Pair with Alkenes,Alkynes, and Carbon Dioxide

The active six-membered cyclo-FLP 6 undergoes a rapid P/B addition reaction to carbon dioxide. At elevated temperature, the resulting heterobicyclo[2.2.2]octane derived product 7 undergoes ring opening and equilibrates with the cyclotetramer (7)₄ . In the large macrocyclic structure, four monomeric six-membered cyclo-FLP units are connected by four CO₂ molecules to form the supramolecular ring system. The P/B cyclo-FLP 6 undergoes a variety of additional cycloaddition reactions.     

Characterization of In Vivo Metabolites of a Potential Anti-obesity Compound,the 3-Methyl-1H-Purine-2,6-Dione Derivative C-11, Employing Ultra-High Performance Liquid Chromatography Coupled with Quadrupole Time-of-Flight Mass Spectrometry

C-11 (2-((7-Ethyl-3-methyl-8-(4-(2-(methyl(pyridin-2-yl)-amino)-ethoxy)phenyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)methyl)benzonitrile-one hydrochloride), which is based on the structure of rosiglitazone, was first synthesized in our laboratory and shown to be a promising anti-obesity drug candidate in our previous pharmacological study. Considering the importance of metabolic fate in vivo in the further development of drug candidates during early drug discovery, it is essential to characterize the metabolism of C-11 in vivo. In this work, a method based on ultra-high performance liquid chromatography combined with quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF-MS) was successfully developed to investigate the in vivo metabolic profile of C-11 in rats. Rat urine, feces, and plasma samples were collected from male Sprague–Dawley rats after intravenous administration of C-11 in a single dose of 30 mg kg⁻¹ body weight. Besides the parent drug, a total of 25 metabolites (including 18 phase I and 7 phase II metabolites) were detected and tentatively identified by comparing their mass spectrometry profiles with those of C-11. This enabled the metabolic pathways of C-11 to be proposed for the first time. Our results revealed that N-depyridinylation, N-demethylation, hydroxylation, glucuronidation, and sulfate conjugation are the predominant metabolic pathways of C-11 in rats. The present study provides systematic information on the metabolism of C-11 in vivo, which should lead to a better understanding of its safety and mechanism of action.

     

Intrinsic Crosslinking and Gel-Breaking Rheokinetics of CMHEC/CTAB Systems

The intrinsic rheokinetics of carboxymethyl hydroxyethyl cellulose and cetyltrimethyl ammonium bromide (CMHEC/CTAB) synergistic fracturing fluid in static crosslinking and gel-breaking processes were studied in this work. Microrheological properties including solid–liquid balance (SLB) and elasticity index (EI) during the static crosslinking and gel-breaking processes were obtained. The effects of temperature on the crosslinking process, concentration of gel-breaker (ammonium persulfate), and temperature on the gel-breaking process were investigated. The novel intrinsic crosslinking and gel-breaking rheokinetics equations were established, respectively. The results show that the crosslinking process can be divided into two stages, and the intrinsic crosslinking rheokinetics equation can well describe EI curves during the static crosslinking process at different temperatures. The EI curves during the gel-breaking process can be well described by the intrinsic gel-breaking rheokinetics equation. The parameters for these two rheokinetics equations are well-defined and reasonable.