A 3D 12‐Ring Zeolite with Ordered 4‐Ring Vacancies Occupied by (H2O)2 Dimers

A germanate zeolite, PKU‐14, with a three‐ dimensional large‐pore channel system was structurally characterized by a combination of high‐resolution powder X‐ray diffraction, rotation electron diffraction, NMR, and IR spectroscopy. Ordered Ge₄O₄ vacancies inside the [4⁶.6¹²] cages has been found in PKU‐14, in which a unique (H₂O)₂ dimer was located at the vacancies and played a structure‐directing role. It is the first time that water clusters are found to be templates for ordered framework vacancies.     

“Click” Chemistry Mildly Stabilizes Bifunctional Gold Nanoparticles for Sensing and Catalysis

A large family of bifunctional 1,2,3‐triazole derivatives that contain both a polyethylene glycol (PEG) chain and another functional fragment (e.g., a polymer, dendron, alcohol, carboxylic acid, allyl, fluorescence dye, redox‐robust metal complex, or a β‐cyclodextrin unit) has been synthesized by facile “click” chemistry and mildly coordinated to nanogold particles, thus providing stable water‐soluble gold nanoparticles (AuNPs) in the size range 3.0–11.2 nm with various properties and applications. In particular, the sensing properties of these AuNPs are illustrated through the detection of an analogue of a warfare agent (i.e., sulfur mustard) by means of a fluorescence “turn‐on” assay, and the catalytic activity of the smallest triazole–AuNPs (core of 3.0 nm) is excellent for the reduction of 4‐nitrophenol in water.     

Improving Site‐Directed RNA Editing In Vitro and in Cell Culture by Chemical Modification of the GuideRNA

Adenosine‐to‐inosine deamination can be re‐addressed to user‐defined mRNAs by applying phosphothioate/2′‐methoxy‐modified guideRNAs. Dense chemical modification of the guideRNA clearly improves performance of the covalent conjugates inside the living cell. Furthermore, careful positioning of a few modifications controls editing selectivity in vitro and was exploited for the challenging repair of the Factor 5 Leiden missense mutation.     

Unprecedented Strong Lewis Bases—Synthesis and Methyl Cation Affinities of Dimethylamino‐Substituted Terpyridines

A versatile method for the synthesis of functionalized 2,2′:6′,2′′‐terpyridines by assembly of the terminal pyridine rings is presented. The cyclization precursors—bis‐β‐ketoenamides—are prepared from 4‐substituted 2,6‐pyridinedicarboxylic acids and acetylacetone or its corresponding enamino ketone. Treatment with trimethylsilyl trifluoromethanesulfonate induces a twofold intramolecular condensation providing an efficient access to 4,4′′‐di‐ and 4,4′,4′′‐trifunctionalized 6,6′′‐dimethyl‐2,2′:6′,2′′‐terpyridines. Using this method, hitherto unknown 4,4′′‐bis(dimethylamino)‐ and 4,4′,4′′‐tris(dimethylamino)terpyridines have been prepared that show remarkably high calculated Lewis basicities.     

π Aromaticity and Three‐Dimensional Aromaticity: Two sides of the Same Coin?

A bridge between classical organic polycyclic aromatic hydrocarbons (PAH) and closo borohydride clusters is established by showing that they share a common origin regulated by the number of valence electrons in an electronic confined space. Application of the proposed electronic confined space analogy (ECSA) method to archetypal PAHs leads to the conclusion that the 4n+2 Wade–Mingos rule for three‐dimensional closo boranes is equivalent to the (4n+2)π Hückel rule for two‐dimensional PAHs. More importantly, use of ECSA allows design of new interesting fused closo boranes which can be a source of inspiration for synthetic chemists.     

通过FGF401的构效关系研究发现一种新颖的FGFR4选择性抑制剂

设计并合成了一系列FGF401类似物以研究其FGFR4抑制、抗肿瘤活性及其构效关系.研究发现了N-(5-氰基-4-(2-甲氧基乙基氨基)吡啶-2-基)-7-甲酰基-6-(N-甲基四氢吡喃-4-甲酰胺)甲基-1,2,3,4-四氢-1,8-萘啶-1-甲酰胺(8ac)不仅在酶和细胞学水平上对FGFR4具有强效的的抑制活性,并表现出了出色的选择性.其活性及选择性优于阳性对照FGF401,并且在HCC (hepatocellular carcinoma)动物移植瘤模型中显著抑制肿瘤生长,还引起了肿瘤萎缩.     

Synthesis of [18F]F-γ-T-3, a Redox-Silent γ-Tocotrienol (γ-T-3) Vitamin E Analogue for Image-Based In Vivo Studies of Vitamin E Biodistribution and Dynamics

Vitamin E, a natural antioxidant, is of interest to scientists, health care pundits and faddists; its nutritional and biomedical attributes may be validated, anecdotal or fantasy. Vitamin E is a mixture of tocopherols (TPs) and tocotrienols (T-3s), each class having four substitutional isomers (α-, β-, γ-, δ-). Vitamin E analogues attain only low concentrations in most tissues, necessitating exacting invasive techniques for analytical research. Quantitative positron emission tomography (PET) with an F-18-labeled molecular probe would expedite access to Vitamin E’s biodistributions and pharmacokinetics via non-invasive temporal imaging. (R)-6-(3-[¹⁸F]Fluoropropoxy)-2,7,8-trimethyl-2-(4,8,12-trimethyltrideca-3,7,11-trien-1-yl)-chromane ([¹⁸F]F-γ-T-3) was prepared for this purpose. [¹⁸F]F-γ-T-3 was synthesized from γ-T-3 in two steps: (i) 1,3-di-O-tosylpropane was introduced at C6-O to form TsO-γ-T-3, and (ii) reaction of this tosylate with [¹⁸F]fluoride in DMF/K₂₂₂. Non-radioactive F-γ-T-3 was synthesized by reaction of γ-T-3 with 3-fluoropropyl methanesulfonate. [¹⁸F]F-γ-T-3 biodistribution in a murine tumor model was imaged using a small-animal PET scanner. F-γ-T-3 was prepared in 61% chemical yield. [¹⁸F]F-γ-T-3 was synthesized in acceptable radiochemical yield (RCY 12%) with high radiochemical purity (>99% RCP) in 45 min. Preliminary F-18 PET images in mice showed upper abdominal accumulation with evidence of renal clearance, only low concentrations in the thorax (lung/heart) and head, and rapid clearance from blood. [¹⁸F]F-γ-T-3 shows promise as an F-18 PET tracer for detailed in vivo studies of Vitamin E. The labeling procedure provides acceptable RCY, high RCP and pertinence to all eight Vitamin E analogues.     

Nucleotide Analogues Bearing a C2′ or C3′-Stereogenic All-Carbon Quaternary Center as SARS-CoV-2 RdRp Inhibitors

The design of novel nucleoside triphosphate (NTP) analogues bearing an all-carbon quaternary center at C2′ or C3′ is described. The construction of this all-carbon stereogenic center involves the use of an intramoleculer photoredox-catalyzed reaction. The nucleoside analogues (NA) hydroxyl functional group at C2′ was generated by diastereoselective epoxidation. In addition, highly enantioselective and diastereoselective Mukaiyama aldol reactions, diastereoselective N-glycosylations and regioselective triphosphorylation reactions were employed to synthesize the novel NTPs. Two of these compounds are inhibitors of the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2, the causal virus of COVID-19.     

烷基修饰寡聚脱氧核苷酸磷酸残基的化学合成及稳定性研究

分别采用格氏试剂和三氯化磷三步取代法合成了4个新的烷基修饰磷酸残基的亚磷酸酰胺单体, 其结构经1H NMR和31P NMR表征. 利用这些单体合成模型序列5'-dTTTx TT-3', 考察了单体及寡聚核苷酸序列在DNA/RNA合成条件下的稳定性, 提出了固相合成含有烷基修饰磷酸残基的寡聚核苷酸序列裂解及脱保护条件.     

白藜芦醇类似物与人血清白蛋白的相互作用

采用荧光光谱、三维荧光光谱、紫外吸收光谱研究白藜芦醇类似物(Z)-2-(3,4-二甲氧苯基)-3-(4-二甲氨基苯基)丙烯腈(HCQ)与人血清白蛋白(HSA)的相互作用,探讨其作为抗肿瘤药物的可能。结果发现HCQ与HSA形成了基态配合物,HCQ主要结合于HSA的位点Ⅰ,与位点Ⅱ也有微量的结合,反应为自发的放热反应,其ΔH、ΔS、ΔG均小于零,二者之间的结合力为氢键或者范德华力,结合常数为104～105数量级。HCQ与HSA的结合使HSA构象发生变化,Trp-214所处的环境疏水性增加,使得其内源性荧光显著降低。说明合成的白藜芦醇类似物能够与人血清白蛋白结合。