Simultaneous observation of halogen-lone pair and halogen-π interactions of ferrocene derivatives under cryogenic conditions.

Contrasting cryosolutions and matrix isolation infrared spectroscopy, we investigate weak intermolecular interactions in complexes of iodo trifluoroethene (C2F3I) and N,N-dimethyl ferrocenyl amine as well as the parent ferrocene. In liquid xenon, solely the C-I⋯N halogen bond can be observed, while the confined environment in solid argon allows for the characterization of C-I⋯π and π⋯π bonded complexes.

Weak yet Decisive: Molecular Halogen Bond and Competing Weak Interactions of Iodobenzene and Quinuclidine.

The halogen bonded adduct between the commonly used constituents quinuclidine and iodobenzene is based on a single weak nitrogen-iodine contact, and the isolation of this adduct was initially unexpected. Iodobenzene does not contain any electron-withdrawing group and therefore represents an unconventional halogen bond donor. Based on excellent diffraction data of high resolution, an electron density study was successfully accomplished and confirmed one of the longest N···I molecular halogen bonds with a distance of 2.9301(4) Å. The topological analysis identified the XB as a directional but weak σ hole interaction and revealed secondary contacts between peripheral regions of opposite charge. These additional contacts and their competition with a nitrogen-based interaction were confirmed by NOESY experiments in solution. Integration enabled us to determine the relative NOE ratios and provided insight regarding the existing interactions.

Combination of Pseudo-Natural Product Design and Formal Natural Product Ring Distortion Yields Stereochemically and Biologically Diverse Pseudo-Sesquiterpenoid Alkaloids.

We describe the synthesis and biological evaluation of a new natural product-inspired compound class obtained by combining the conceptually complementary pseudo-natural product (pseudo-NP) design strategy and a formal adaptation of the complexity-to-diversity ring distortion approach. Fragment-sized α-methylene-sesquiterpene lactones, whose scaffolds can formally be viewed as related to each other or are obtained by ring distortion, were combined with alkaloid-derived pyrrolidine fragments by means of highly selective stereocomplementary 1,3-dipolar cycloaddition reactions. The resulting pseudo-sesquiterpenoid alkaloids were found to be both chemically and biologically diverse, and their biological performance distinctly depends on both the structure of the sesquiterpene lactone-derived scaffolds and the stereochemistry of the pyrrolidine fragment. Biological investigation of the compound collection led to the discovery of a novel chemotype inhibiting Hedgehog-dependent osteoblast differentiation.

Design, Synthesis, and Biological Evaluation of Chemically and Biologically Diverse Pyrroquinoline Pseudo Natural Products.

Natural product (NP) structures are a rich source of inspiration for the discovery of new biologically relevant chemical matter. In natural product inspired pseudo-NPs, NP-derived fragments are combined de novo in unprecedented arrangements. Described here is the design and synthesis of a 155-member pyrroquinoline pseudo-NP collection in which fragments characteristic of the tetrahydroquinoline and pyrrolidine NP classes are combined with eight different connectivities and regioisomeric arrangements. Cheminformatic analysis and biological evaluation of the compound collection by means of phenotyping in the morphological "cell painting" assay followed by principal component analysis revealed that the pseudo-NP classes are chemically diverse and that bioactivity patterns differ markedly, and are dependent on connectivity and regioisomeric arrangement of the fragments.

RhIII -Catalyzed C-H Activation of Aryl Hydroxamates for the Synthesis of Isoindolinones.

RhIII -catalyzed C-H functionalization reaction yielding isoindolinones from aryl hydroxamates and ortho-substituted styrenes is reported. The reaction proceeds smoothly under mild conditions at room temperature, and tolerates a range of functional groups. Experimental and computational investigations support that the high regioselectivity observed for these substrates results from the presence of an ortho-substituent embedded in the styrene. The resulting isoindolinones are valuable building blocks for the synthesis of bioactive compounds. They provide easy access to the natural-product-like compounds, isoindolobenzazepines, in a one-pot two-step reaction. Selected isoindolinones inhibited Hedgehog (Hh)-dependent differentiation of multipotent murine mesenchymal progenitor stem cells into osteoblasts.

Quantifying guideline adherence in mucormycosis management using the EQUAL score.

OBJECTIVES: Mucormycosis is a difficult-to-diagnose life-threatening disease with high morbidity and mortality. Adherence to guidelines that lead through complex management and support clinical decisions is however rarely reported. By applying the EQUAL Score, our study evaluates the management of mucormycosis at the University Hospital of Cologne, Germany. METHODS: We performed a retrospective chart review of patients with mucormycosis at the University Hospital of Cologne. Data collection comprised items for quality assessment in mucormycosis management according to the EQUAL Mucormycosis Score and economics. RESULTS: Of 29 patients identified, 27 were documented retrospectively. Eight patients of 18 with neutropenia (>10 days) or receiving allogeneic stem cell transplantation (44.4%) received mould active prophylaxis. Chest CT was done in 21 patients (77.8%), while BAL and direct microscopy of BAL fluid was performed in 22 patients (81.5%), culture in 22 (81.5%) and fungal PCR in 24 (88.9%). First-line treatment was liposomal amphotericin B in 19 patients (70.4%). Isavuconazole or posaconazole with therapeutic drug monitoring was used in four (14.8%) and in one patient (3.7%), respectively. In our cohort, crude mortality was 51.9% (n = 14) with a median survival time of 113 days. During the management of the 27 patients, 450 points (53.8%) of the maximum EQUAL Mucormycosis Score were achieved (median 15 points, range 6-30). CONCLUSIONS: We observed management of mucormycosis aligning with current guidelines and hope to encourage other groups to use the EQUAL Score in routine clinical settings. Future studies will evaluate whether guideline adherence in mucormycosis management improves patient outcome.

Aminopotassiation by Mixed Potassium/Lithium Amides: A Synthetic Path to Difficult to Access Phenethylamine Derivates.

Insights gained from a comparison of aminometalation reactions with lithium amides, potassium amides and mixed lithium/potassium amides are presented. A combination of structural characterization, DFT calculations and electrophile reactions of aminometalated intermediates has shown the advantages of using a mixed metal strategy. While potassium amides fail to add, the lithium amides are uncontrollable and eliminated, yet the mixed K/Li amides deliver the best of both systems. Aminopotassiation proceeds to form the alkylpotassium species which has enhanced stability over its lithium counterpart allowing for its isolation and thereby its further characterization.

A Scaffold-Diversity Synthesis of Biologically Intriguing Cyclic Sulfonamides.

A "branching-folding" synthetic strategy that affords a range of diverse cyclic benzo-sulfonamide scaffolds is presented. Whereas different annulation reactions on common ketimine substrates build the branching phase of the scaffold synthesis, a common hydrogenative ring-expansion method, facilitated by an increase of the ring-strain during the branching phase, led to sulfonamides bearing medium-sized rings in a folding pathway. Cell painting assay was successfully employed to identify tubulin targeting sulfonamides as novel mitotic inhibitors.

Unravelling the Synthesis and Chemistry of Stable, Acyclic, and Double-Deficient 1,3-Butadienes: An endo-Selective Diels-Alder Route to Hedgehog Pathway Inhibitors.

The first synthetic access to stable and acyclic 1,3-butadienes with two electron-withdrawing carbonyl groups and their potential to deliver new molecular scaffolds through intriguing endo-selective Diels-Alder cycloadditions are presented. The bicyclic scaffolds produced through the cycloaddition chemistry of electron-deficient dienes afforded potent Hedgehog signaling pathway inhibitors.

A synergistic Rh(I)/organoboron-catalysed site-selective carbohydrate functionalization that involves multiple stereocontrol.

Site-selective functionalization is a core synthetic strategy that has broad implications in organic synthesis. Particularly, exploiting chiral catalysis to control site selectivity in complex carbohydrate functionalizations has emerged as a leading method to unravel unprecedented routes into biologically relevant glycosides. However, robust catalytic systems available to overcome multiple facets of stereoselectivity challenges to this end still remain scarce. Here we report a synergistic chiral Rh(I)- and organoboron-catalysed protocol, which enables access into synthetically challenging but biologically relevant arylnaphthalene glycosides. Our method depicts the employment of chiral Rh(I) catalysis in site-selective carbohydrate functionalization and showcases the utility of boronic acid as a compatible co-catalyst. Crucial to the success of our method is the judicious choice of a suitable organoboron catalyst. We also determine that exquisite multiple aspects of stereocontrol, including enantio-, diastereo-, regio- and anomeric control and dynamic kinetic resolution, are concomitantly operative.

Gauging the Strength of the Molecular Halogen Bond via Experimental Electron Density and Spectroscopy.

Strong and weak halogen bonds (XBs) in discrete aggregates involving the same acceptor are addressed by experiments in solution and in the solid state. Unsubstituted and perfluorinated iodobenzenes act as halogen donors of tunable strength; in all cases, quinuclidine represents the acceptor. NMR titrations reliably identify the strong intermolecular interactions in solution, with experimental binding energies of approx. 7 kJ/mol. Interaction of the σ hole at the halogen donor iodine leads to a redshift in the symmetric C-I stretching vibration; this shift reflects the interaction energy in the halogen-bonded adducts and may be assessed by Raman spectroscopy in condensed phase even for weak XBs. An experimental picture of the electronic density for the XBs is achieved by high-resolution X-ray diffraction on suitable crystals. Quantum theory of atoms in molecules (QTAIM) analysis affords the electron densities and energy densities in the bond critical points of the halogen bonds and confirms stronger interaction for the shorter contacts. For the first time, the experimental electron density shows a significant effect on the atomic volumes and Bader charges of the quinuclidine N atoms, the halogen-bond acceptor: strong and weak XBs are reflected in the nature of their acceptor atom. Our experimental findings at the acceptor atom match the discussed effects of halogen bonding and thus the proposed concepts in XB activated organocatalysis.

Crystal structure of N,N,N',N'-tetra-methyl-ethane-di-amine.

The title compound N,N,N',N'-tetra-methyl-ethanedi-amine, C6H16N2, is a bidentate amine ligand commonly used in organolithium chemistry for deaggregation. Crystals were grown at 243 K from n-pentane solution. The complete mol-ecule is generated by a crystallographic center of symmetry and the conformation of the di-amine is anti-periplanar. To investigate the inter-molecular inter-actions, a Hirshfeld surface analysis was performed. It showed that H⋯H (van der Waals) inter-actions dominate with a contact percentage of 92.3%.

Telomerase-targeting compounds Imetelstat and 6-thio-dG act synergistically with chemotherapy in high-risk neuroblastoma models.

BACKGROUND: The majority of high-risk neuroblastomas harbor telomerase activity, and telomerase-interacting compounds, such as 6-thio-2'-deoxyguanosine (6-thio-dG), have been found to impair the growth of telomerase-positive neuroblastoma cell lines. It has remained unclear, however, how such drugs can be combined with other compounds used in current treatment concepts for neuroblastoma patients. METHODS: Growth-inhibitory effects of varying concentrations of 6-thio-dG in combination with etoposide, doxorubicin or ceritinib were determined in eight telomerase-positive neuroblastoma cell lines with distinct genetic backgrounds. Tumor growth inhibition of subcutaneous xenografts from three different cell lines was assessed upon treatment with 6-thio-dG, the competitive telomerase inhibitor imetelstat, etoposide, or combinations of these compounds. RESULTS: Robust synergistic anti-tumor effects were observed for combinations of 6-thio-dG and etoposide or doxorubicin, but not for 6-thio-dG and ceritinib, in telomerase-positive neuroblastoma cell lines in vitro. Treatment of mouse xenografts with combinations of 6-thio-dG and etoposide significantly attenuated tumor growth and improved mouse survival over etoposide alone in two of three cell line models. Treatment of xenograft tumors by imetelstat monotherapy decreased telomerase activity by roughly 50% and significantly improved survival over control in all three models, whereas treatment with imetelstat plus etoposide led to enhanced survival over etoposide monotherapy in one model. Mechanistically, the synergistic effect was found to be due to both increased apoptosis and cell cycle arrest. CONCLUSION: Our study indicates that telomerase is an actionable target in telomerase-positive neuroblastoma, and demonstrates that combination therapies including telomerase-interacting compounds may improve the efficacy of established cytotoxic drugs. Targeting telomerase may thus represent a therapeutic option in high-risk neuroblastoma patients.

Crystal structure of 2-methyl-1,2,3,4-tetra-hydro-iso-quinoline trihydrate.

The crystal structure of the title compound, C10H13N·3H2O, a heterocyclic amine, was determined in the presence of water. The compound co-crystallizes with three water mol-ecules in the asymmetric unit, which leads to the formation of hydrogen bonding in the crystal.

Crystal structures of [(N,N-di-methyl-amino)-meth-yl]ferrocene and (R p,R p)-bis-{2-[(di-methyl-amino)-meth-yl]ferrocen-yl}di-methyl-silane.

The title compound [(N,N-di-methyl-amino)-meth-yl]ferrocene, [Fe(C5H5)(C8H12N)], (1), is an inter-esting starting material for the synthesis of planar chiral 1,2-disubstituted ferrocenes, as demonstrated by the preparation of (R p,R p)-bis-{2-[(di-methyl-amino)-meth-yl]ferrocen-yl}di-methyl-silane, [Fe2(C5H5)2(C18H18N2Si)], (2), from the li-thia-ted derivative of 1. The configuration of the lithium compound is unchanged after the substitution reaction and the chirality is preserved in space group P212121. In both compounds, the Cp rings adopt eclipsed conformations. Hirshfeld surface analysis was used to investigate the inter-molecular inter-actions, and showed that H⋯H (van der Waals) inter-actions dominate in both structures with contact percentages of 83.9 and 88.4% for 1 and 2, respectively.

Enantioselective Synthesis of Five-Membered-Ring Atropisomers with a Chiral Rh(III) Complex.

Axially chiral atropisomeric compounds are widely applied in asymmetric catalysis and medicinal chemistry, and efficient methods for their synthesis are in high demand. This applies in particular to atropisomers derived from five-membered aromatic rings because their lower barrier for rotation among the biaryl axis limits their asymmetric synthesis. We report here an enantioselective C-H functionalization method using our chiral RhJasCp complex for the synthesis of the biaryl atropisomer types that can be accessed from three different five-membered-ring heterocycles.

Telomerase Is a Prognostic Marker of Poor Outcome and a Therapeutic Target in Neuroblastoma.

PURPOSE: Telomere maintenance is a hallmark of high-risk neuroblastoma; however, the contribution of telomerase and alternative lengthening of telomeres (ALT) to clinical phenotypes has remained unclear. We aimed to determine the clinical relevance of telomerase activation versus ALT as biomarkers in pretreatment neuroblastoma and to assess the potential value of telomerase as a therapeutic target. MATERIALS AND METHODS: The genomic status of TERT and MYCN was assessed in 457 pretreatment neuroblastomas by fluorescence in situ hybridization. ALT was examined in 273 of 457 tumors by detection of ALT-associated promyelocytic leukemia nuclear bodies, and TERT expression was determined by microarrays in 223 of these. Cytotoxic effects of telomerase-interacting compounds were analyzed in neuroblastoma cell lines in vitro and in vivo. RESULTS: We detected TERT rearrangements in 46 of 457 cases (10.1%), MYCN amplification in 93 of 457 cases (20.4%), and elevated TERT expression in tumors lacking TERT or MYCN alterations in 10 of 223 cases (4.5%). ALT activation was found in 49 of 273 cases (17.9%). All these alterations occurred almost mutually exclusively and were associated with unfavorable prognostic variables and adverse outcome. The presence of activated telomerase (ie, TERT rearrangements, MYCN amplification, or high TERT expression without these alterations) was associated with poorest overall survival and was an independent prognostic marker in multivariable analyses. We also found that the telomerase-interacting compound 6-thio-2'-deoxyguanosine effectively inhibited viability and proliferation of neuroblastoma cells bearing activated telomerase. Similarly, tumor growth was strongly impaired upon 6-thio-2'-deoxyguanosine treatment in telomerase-positive neuroblastoma xenografts in mice. CONCLUSION: Our data suggest telomerase activation and ALT define distinct neuroblastoma subgroups with adverse outcome and that telomerase may represent a promising therapeutic target in many high-risk neuroblastomas.

Crystal structures of di-aquadi-µ-hydroxido-tris-[tri-methyl-tin(IV)] diformatotri-methyl-stannate(IV) and di-µ-hydroxido-tris-[tri-methyl-tin(IV)] chloride monohydrate.

The title compounds, [Sn3(CH3)9(OH)2(H2O)2][Sn(CH3)3(CHO2)2] (1) and [Sn3(CH3)9(OH)2]Cl·H2O (2), are partially condensed products of hydrolysed tri-methyl-tin chloride. In the structures of 1 and 2, short cationic tris-tannatoxanes (C9H29O2Sn3) are bridged by a diformatotri-methyl-tin anion or a chloride anion, respectively. Hydrogen bridges are present and supposedly stabilize these structures against further polymerization to the known polymeric tri-methyl-tin hydroxide. Especially noteworthy is that the formate present in this structure was formed from atmospheric CO2.