Crystal growth and characterisation of new organic nonlinear optical materials: 6-cyano and 6-nitro-2,2-dimethyl-3,4-epoxychroman

Two chiral organic nonlinear optical materials, (3S,4S)-(−)-6-cyano-2,2-dimethyl-3,4-epoxychroman (1) and (3R,4R)-(+)-6-nitro-2,2-dimethyl-3,4-epoxychroman (2), have been grown into single crystals of cm³-size. Although both compounds crystallise in the orthorhombic P2₁2₁2₁ space group, they are not isomorphous and their crystal packings are quite different. Angle tuned type II phase-matched second harmonic generation between 0.8 and 1.064 μm has been evidenced, with effective nonlinear coefficients d_eff of 1 and 5 pm/V at 0.96 μm for 1 and 2, respectively. These values are in agreement with those estimated in the oriented gas model approximation using EFISH first order hyperpolarisability values (β₀=2.6 and 4.0×10⁻³⁰ esu for 1 and 2, respectively).     

The synthesis of [Fe(CO)3(η1-dppm) {Sn(n-Bu)2}]2 by silicon-tin exchange,its crystal structure and its use as a metallodiphosphine ligand

The reaction of the siloxyl containing ferrate [Fe(CO)₃( ¹-dppm){Si(OMe)₃}]^–,1 (dppm = Ph₂PCH₂PPh₂) with Sn(OAc)₂(n-Bu)₂ has yielded the new dimeric complex [Fe(CO)₃( ¹-dppm){µ-Sn(n-Bu)₂}]₂, 3 in 89% yield. Compound3 was characterized crystallographically and was found to be a centrosym-etrical molecule with a rhomboidal Fe₂Sn₂ cluster at the center. Each iron atom contains me ¹-dppm ligand. Compound3 was found to react with [Pd(dmba) (µ-Cl)]₂ (dmba=dimethylbenzylamine) to yield the new complexmer-[Fe(CO)₃{Sn(n-Bu)₂}(µ-dppm)Pd(dmba)Cl]₂, 4 by attachment of a palla-dium grouping to each of the uncoordinated phosphorus atoms in 3. Crystal data for 3: space groupP ,a=11.399(2) Å, 6=15.98(3) Å, c=10.869(3) Å, =94.10(2)°.=100.56(2)°, =69.35(1)°,Z=2, 3533 reflections,R=0.034.     

Potent inhibitors of the hepatitis C virus NS3 protease: design and synthesis of macrocyclic substrate-based beta-strand mimics

The virally encoded NS3 protease is essential to the life cycle of the hepatitis C virus (HCV), an important human pathogen causing chronic hepatitis, cirrhosis of the liver, and hepatocellular carcinoma. The design and synthesis of 15-membered ring beta-strand mimics which are capable of inhibiting the interactions between the HCV NS3 protease enzyme and its polyprotein substrate will be described. The binding interactions between a macrocyclic ligand and the enzyme were explored by NMR and molecular dynamics, and a model of the ligand/enzyme complex was developed.     

Improved broad-spectrum antibiotics against Gram-negative pathogens via darobactin biosynthetic pathway engineering

The development of new antibiotics is imperative to fight increasing mortality rates connected to infections caused by multidrug-resistant (MDR) bacteria. In this context, Gram-negative pathogens listed in the WHO priority list are particularly problematic. Darobactin is a ribosomally produced and post-translationally modified bicyclic heptapeptide antibiotic selectively killing Gram-negative bacteria by targeting the outer membrane protein BamA. The native darobactin A producer Photorhabdus khanii HGB1456 shows very limited production under laboratory cultivation conditions. Herein, we present the design and heterologous expression of a synthetically engineered darobactin biosynthetic gene cluster (BGC) in Escherichia coli to reach an average darobactin A production titre of 13.4 mg L⁻¹. Rational design of darA variants, encoding the darobactin precursor peptide with altered core sequences, resulted in the production of 13 new ‘non-natural’ darobactin derivatives and 4 previously hypothetical natural darobactins. One of the non-natural compounds, darobactin 9, was more potent than darobactin A, and showed significantly improved activity especially against Pseudomonas aeruginosa (0.125 μg mL⁻¹) and Acinetobacter baumannii (1–2 μg mL⁻¹). Importantly, it also displayed superior activity against MDR clinical isolates of E. coli (1–2 μg mL⁻¹) and Klebsiella pneumoniae (1–4 μg mL⁻¹). Independent deletions of genes from the darobactin BGC showed that only darA and darE, encoding a radical forming S-adenosyl-l-methionine-dependent enzyme, are required for darobactin formation. Co-expression of two additional genes associated with the BGCs in hypothetical producer strains identified a proteolytic detoxification mechanism as a potential self-resistance strategy in native producers. Taken together, we describe a versatile heterologous darobactin platform allowing the production of unprecedented active derivatives in good yields, and we provide first experimental evidence for darobactin biosynthesis processes.

Heterologous expression of a synthetically engineered darobactin gene cluster in E. coli yields new darobactin derivatives with improved anti-Gram-negative activity. Targeted gene deletions provide first insights into biosynthetic steps.     

Polyphenol-Enriched Blueberry Preparation Controls Breast Cancer Stem Cells by Targeting FOXO1 and miR-145

Scientific evidence supports the early deregulation of epigenetic profiles during breast carcinogenesis. Research shows that cellular transformation, carcinogenesis, and stemness maintenance are regulated by epigenetic-specific changes that involve microRNAs (miRNAs). Dietary bioactive compounds such as blueberry polyphenols may modulate susceptibility to breast cancer by the modulation of CSC survival and self-renewal pathways through the epigenetic mechanism, including the regulation of miRNA expression. Therefore, the current study aimed to assay the effect of polyphenol enriched blueberry preparation (PEBP) or non-fermented blueberry juice (NBJ) on the modulation of miRNA signature and the target proteins associated with different clinical-pathological characteristics of breast cancer such as stemness, invasion, and chemoresistance using breast cancer cell lines. To this end, 4T1 and MB-MDM-231 cell lines were exposed to NBJ or PEBP for 24 h. miRNA profiling was performed in breast cancer cell cultures, and RT-qPCR was undertaken to assay the expression of target miRNA. The expression of target proteins was examined by Western blotting. Profiling of miRNA revealed that several miRNAs associated with different clinical-pathological characteristics were differentially expressed in cells treated with PEBP. The validation study showed significant downregulation of oncogenic miR-210 expression in both 4T1 and MDA-MB-231 cells exposed to PEBP. In addition, expression of tumor suppressor miR-145 was significantly increased in both cell lines treated with PEBP. Western blot analysis showed a significant increase in the relative expression of FOXO1 in 4T1 and MDA-MB-231 cells exposed to PEBP and in MDA-MB-231 cells exposed to NBJ. Furthermore, a significant decrease was observed in the relative expression of N-RAS in 4T1 and MDA-MB-231 cells exposed to PEBP and in MDA-MB-231 cells exposed to NBJ. Our data indicate a potential chemoprevention role of PEBP through the modulation of miRNA expression, particularly miR-210 and miR-145, and protection against breast cancer development and progression. Thus, PEBP may represent a source for novel chemopreventative agents against breast cancer.     

Palladium-Catalyzed Cyclization of a Pyryne Precursor to Higher Pyrenylenes

The palladium catalyzed cyclotrimerization of ortho-silylaryl triflates as aryne precursors is meanwhile an established method to synthesize polycyclic aromatic hydrocarbons (PAHs) with triphenylene cores. During the palladium-catalyzed reaction of a pyrene with an o-silylaryl triflate moiety in the K-region higher homologues with central eight- and ten-membered rings (the pyrenylenes) were found, besides the expected trimer and a protocol was developed to isolate all members of this series. This unprecedented new class of PAHs was fully investigated by all means, including X-ray diffraction of single-crystals, UV/Vis and fluorescence spectroscopy and theoretical calculations. Supported by density-functional theory (DFT) calculations, a mechanism of all higher cyclooligomers is proposed.     

Femtosecond Spectroscopy and Nonlinear Optical Properties of aza-BODIPY Derivatives in Solution

The fast relaxation processes in the excited electronic states of functionalized aza-boron-dipyrromethene (aza-BODIPY) derivatives ( 1 – 4 ) were investigated in liquid media at room temperature, including the linear photophysical, photochemical, and nonlinear optical (NLO) properties. Optical gain was revealed for nonfluorescent derivatives 3 and 4 in the near infrared (NIR) spectral range under femtosecond excitation. The values of two-photon absorption (2PA) and excited-state absorption (ESA) cross-sections were obtained for 1–4 in dichloromethane using femtosecond Z-scans, and the role of bromine substituents in the molecular structures of 2 and 4 is discussed. The nature of the excited states involved in electronic transitions of these dyes was investigated using quantum-chemical TD-DFT calculations, and the obtained spectral parameters are in reasonable agreement with the experimental data. Significant 2PA (maxima cross-sections ∼2000 GM), and large ESA cross-sections ∼10⁻²⁰ m² of these new aza-BODIPY derivatives 1–4 along with their measured high photostability reveal their potential for photonic applications in general and optical limiting in particular.     

Comparing the 2,2′‐Biphenylenedithiophosphinate Binding of Americium with Neodymium and Europium

Advancing our understanding of the minor actinides (Am, Cm) versus lanthanides is key for developing advanced nuclear‐fuel cycles. Herein, we describe the preparation of (NBu₄)Am[S₂P(^tBu₂C₁₂H₆)]₄ and two isomorphous lanthanide complexes, namely one with a similar ionic radius (i.e., Nd^III) and an isoelectronic one (Eu^III). The results include the first measurement of an Am?S bond length, with a mean value of 2.921(9) Å, by single‐crystal X‐ray diffraction. Comparison with the Eu^III and Nd^III complexes revealed subtle electronic differences between the complexes of Am^III and the lanthanides.     

Synthesis, structures, optical properties, and TD-DFT studies of donor-π-conjugated dipicolinic acid/ester/amide ligands

A series of 2,6- and 4-functionalized dipicolinic acid, ester, or amide featuring π-conjugated substituents such as donor-(phenyl or fluorenyl)-acetylene groups have been synthesized. Four crystallographic structures are reported. The influence of the substituent position, the nature of the donor group, and the conjugated backbone as well as the role of the pyridinic side arms on the absorption and emission properties are studied and discussed on the basis of TD-DFT calculations.