Comparison of different density functional theory methods for the calculation of vibrational circular dichroism spectra.

The determination of the absolute configuration (AC) of an organic molecule is still a challenging task for which the combination of spectroscopic with quantum-mechanical methods has become a promising approach. In this study, we investigated the accuracy of DFT methods (480 overall combinations of 15 functionals, 16 basis sets, and 2 solvation models) to calculate the VCD spectra of six chiral organic molecules in order to benchmark their capability to facilitate the determination of the AC.

Total synthesis and biological evaluation of seven new anti-inflammatory oxacyclododecindione-type macrolactones.

Through variation of our previously published total synthesis of two highly active anti-inflammatory macrolactones from the oxacyclododecindione family (J. Tauber, M. Rohr, T. Walter, G. Erkel and T. Opatz, Org. Biomol. Chem., 2015, 13, 7813-7821), seven new representatives of this compound class were prepared. Substitution of the 14-hydroxy group in oxacyclododecindione with a methyl substituent provided a readily accessible non-natural analogue which has similar pharmacological properties to the scarcely available natural product. Since the producible amount of substance is therefore no longer restricted by low fermentation yields, extensive in vivo studies become possible for the first time. Based on this finding, further investigations on structure-activity relationships were undertaken by variation of the halogen atom, which showed that exchange or omission of the chloro substituent led to significantly lower binding affinities. Furthermore, it was found that elongation of the crucial and characteristic aliphatic side chain at C-10 also increased the IC50 value in the biological assays of interest.

Lipoic Acid Synergizes with Antineoplastic Drugs in Colorectal Cancer by Targeting p53 for Proteasomal Degradation.

Lipoic acid (LA) is a redox-active disulphide compound, which functions as a pivotal co-factor for mitochondrial oxidative decarboxylation. LA and chemical derivatives were shown to target mitochondria in cancer cells with altered energy metabolism, thereby inducing cell death. In this study, the impact of LA on the tumor suppressor protein p53 was analyzed in various colorectal cancer (CRC) cell lines, with a focus on the mechanisms driving p53 degradation. First, LA was demonstrated to trigger the depletion of both wildtype and mutant p53 protein in all CRC cells tested without influencing its gene expression and preceded LA-triggered cytotoxicity. Depletion of p53 coincided with a moderate, LA-dependent ROS production, but was not rescued by antioxidant treatment. LA induced the autophagy receptor p62 and differentially modulated autophagosome formation in CRC cells. However, p53 degradation was not mediated via autophagy as shown by chemical inhibition and genetic abrogation of autophagy. LA treatment also stabilized and activated the transcription factor Nrf2 in CRC cells, which was however dispensable for p53 degradation. Mechanistically, p53 was found to be readily ubiquitinylated and degraded by the proteasomal machinery following LA treatment, which did not involve the E3 ubiquitin ligase MDM2. Intriguingly, the combination of LA and anticancer drugs (doxorubicin, 5-fluorouracil) attenuated p53-mediated stabilization of p21 and resulted in synergistic killing in CRC cells in a p53-dependant manner.

Bisbenzylisoquinoline Alkaloids.

The present review covers the literature on bisbenzylisoquinoline alkaloids from 1999 through early 2018. About 500 natural products belong to this large alkaloid class, of which 65 were characterized for the first time in the period covered by this chapter. The review comprises a classification of bisbenzylisoquinoline alkaloids and gives an overview of the principal biosynthetic pathways. Furthermore, a list of the novel natural products as well as their available analytical data are included in this chapter. Special emphasis is given to the progress in the total synthesis of bisbenzylisoquinoline alkaloids. To accommodate the drastically increased number of publications concerning the biological and pharmacological evaluation, an overview on the most important biological findings is provided.

Polyethylene bio-degradation by caterpillars?

In their recent paper on the degradation of polyethylene by caterpillars of the wax moth Galleria melonella, Bombelli et al.[1] report various experiments, including microscopic and spectroscopic data which the authors believe support the chemical digestion of the polymers by these insects. While the biodegradation of mostly inert artificial polymers is definitely a very interesting research field, we must respectfully disagree with the methodology and conclusions from this paper.

Absolute Configuration Determination of 2,3-Dihydro-1H,5H-pyrazolo[1,2-a]pyrazoles Using Chiroptical Methods at Different Wavelengths.

A correlation between the absolute configuration and chiroptical properties of nonracemic 1,6,7-trisubstituted 2,3-dihydro-1H,5H-pyrazolo[1,2-a]pyrazoles was studied. A series of 16 novel representatives were prepared by Cu-catalyzed [3 + 2] cycloadditions of racemic (Z)-2-benzylidene-5-oxopyrazolidin-2-ium-1-ides to tert-butyl (S)-(3-oxopent-4-yn-2-yl)carbamate, and their structures were determined by NMR, VCD, ECD, and X-ray diffraction. A clear correlation between the sign of specific rotation and configuration at position C(1) allows for easy determination of the absolute configuration of 1,6,7-trisubstituted 2,3-dihydro-1H,5H-pyrazolo[1,2-a]pyrazoles by ECD and NMR. While VCD, requiring milligram quantities, allowed the determination of the correct relative and absolute configuration without additional information from other methods, the stereochemical analysis by ECD required knowledge of the relative configuration derived from NMR at a comparable computational level.

Characterization of the synthetic cannabinoid MDMB-CHMCZCA.

The synthetic cannabinoid MDMB-CHMCZCA was characterized by various spectroscopic techniques including NMR spectroscopy and tandem mass spectrometry. The synthetic sample was found to be of S-configuration by VCD spectroscopy and comparison of the data with DFT calculations, while ECD spectroscopy was found to be inconclusive in this case. The enantiomeric purity of samples from test purchases and police seizures was assessed by a self-developed chiral HPLC method.

An efficient and practical synthesis of [2-(11)C]indole via superfast nucleophilic [(11)C]cyanation and RANEY® Nickel catalyzed reductive cyclization.

A rapid method for the synthesis of carbon-11 radiolabeled indole was developed using a sub-nanomolar quantity of no-carrier-added [(11)C]cyanide as radio-precursor. Based upon a reported synthesis of 2-(2-nitrophenyl)acetonitrile (), a highly reactive substrate 2-nitrobenzyl bromide () was evaluated for nucleophilic [(11)C]cyanation. Additionally, related reaction conditions were explored with the goal of obtaining of highly reactive 2-(2-nitrophenyl)-[1-(11)C]acetonitrile () while inhibiting its rapid conversion to 2,3-bis(2-nitrophenyl)-[1-(11)C]propanenitrile (). Next, a RANEY® Nickel catalyzed reductive cyclization method was utilized for synthesizing the desired [2-(11)C]indole with hydrazinium monoformate as the active reducing agent. Extensive and iterative screening of basicity, temperature and stoichiometry was required to overcome the large stoichiometry bias that favored 2-nitrobenzylbromide () over [(11)C]cyanide, which both caused further alkylation of the desired nitrile and poisoned the RANEY® Nickel catalyst. The result is an efficient two-step, streamlined method to reliably synthesize [2-(11)C]indole with an entire radiochemical yield of 21 ± 2.2% (n = 5, ranging from 18-24%). The radiochemical purity of the final product was >98% and specific activity was 176 ± 24.8 GBq µmol(-1) (n = 5, ranging from 141-204 GBq µmol(-1)). The total radiosynthesis time including product purification by semi-preparative HPLC was 50-55 min from end of cyclotron bombardment.

Blue laser light increases perfusion of a skin flap via release of nitric oxide from hemoglobin.

It has recently been shown that nitrosyl complexes of hemoglobin (NO-Hb) are sensitive to low-level blue laser irradiation, suggesting that laser irradiation can facilitate the release of biologically active nitric oxide (NO), which can affect tissue perfusion. The aim of this study was to evaluate the therapeutic value of blue laser irradiation for local tissue perfusion after surgical intervention. Blood was withdrawn from a rat, exposed to NO and infused back to the same rat or used for in vitro experiments. In vitro, an increase of NO-Hb levels (electron paramagnetic resonance spectroscopy) up to 15 microM in rat blood did not result in the release of detectable amounts of NO (NO selective electrode). Blue laser irradiation of NO-Hb in blood caused decomposition of NO-Hb complexes and release of free NO. Systemic infusion of NO-Hb in rats affected neither systemic circulation (mean arterial pressure) nor local tissue perfusion (Doppler blood flow imaging system). In contrast, a clear enhancement of local tissue perfusion was observed in epigastric flap when elevated NO-Hb levels in blood were combined with local He-Cd laser irradiation focused on the left epigastric artery. The enhancement of regional tissue perfusion was not accompanied by any detectable changes in systemic circulation. This study demonstrates that blue laser irradiation improves local tissue perfusion in a controlled manner stimulating NO release from NO-Hb complexes.

The attenuation of hepatic microcirculatory alterations by exogenous substitution of nitric oxide by s-nitroso-human albumin after hemorrhagic shock in the rat.

Hepatic microcirculatory disorders such as narrowing of sinusoids after hemorrhagic shock play a major role in the pathogenesis of organ failure. It is known that the balance of vasoactive mediators such as endothelin and nitric oxide (NO) regulate microvascular perfusion, including the diameter of hepatic sinusoids. The present study was designed to evaluate the role of exogenous substitution of NO by S-nitroso-albumin (S-NO-HSA) in the prevention of pathophysiological alterations of hepatic microcirculation. Anesthetized Sprague-Dawley rats were instrumented for invasive hemodynamic monitoring. Hemorrhagic shock was induced by bleeding to a mean arterial pressure (MAP) of 40 mmHg and was maintained for 60 min. Thereafter, the animals were resuscitated with shed blood and Ringer's solution. During the first hour of resuscitation, S-NO-HSA or pure HSA was infused continuously (10 micromol/kg/h) and hepatic microcirculation was detected by intravital epifluorescence microscopy either 5 or 24 h after the insult. Results were compared with a sham-treated group (n = 6-8 per group). Shock-induced microcirculatory narrowing of sinusoids was significantly reduced in the S-NO-HSA group compared with the HSA group both at 5 and 24 h (HSA: 9.3 +/- 0.2 microm; S-NO-HSA: 12.1 +/- 0.2 microm, P < 0.05). Sinusoidal perfusion was significantly higher in the S-NO-HSA group than in the HSA group (HSA: 50,934 +/- 1,382 microm3/s; S-NO-HSA: 78,120 +/- 2,348 microm3/s, P < 0.05). Reversible leukocyte adhesion to sinusoidal endothelium, an indicator of the inflammatory response, was significantly reduced in the S-NO-HAS-treated group. The findings of this study in a rat model of hemorrhagic shock suggest that NO substitution by S-NO-HSA during resuscitation attenuates both early and late hepatic microcirculatory disturbances as well as the increase in leukocyte adherence.