meso-Tetrahexyl-7,8-dihydroxychlorin and Its Conversion to ß-Modified Derivatives.

meso-Tetrahexylporphyrin was converted to its corresponding 7,8-dihydroxychlorin using an osmium tetroxide-mediated dihydroxylation strategy. Its diol moiety was shown to be able to undergo a number of subsequent oxidation reactions to form a chlorin dione and porpholactone, the first meso-alkylporphyrin-based porphyrinoid containing a non-pyrrolic building block. Further, the diol chlorin was shown to be susceptible to dehydration, forming the porphyrin enol that is in equilibrium with its keto-chlorin form. The meso-hexylchlorin dione could be reduced and it underwent mono- and bis-methylation reactions using methyl-Grignard reagents, and trifluoromethylation using the Ruppert-Prakash reagent. The optical and spectroscopic properties of the products are discussed and contrasted to their corresponding meso-aryl derivatives (where known). This contribution establishes meso-tetrahexyl-7,8-dihydroxychlorins as a new and versatile class of chlorins that is susceptible to a broad range of conversions to generate functionalized chlorins and a pyrrole-modified chlorin analogue.

Synthesis, in Vitro Cholinesterase Inhibition, Molecular Docking, DFT, and ADME Studies of Novel 1,3,4-Oxadiazole-2-Thiol Derivatives.

A series of 1,3,4-oxadiazole-2-thiol derivatives bearing various alkyl or aryl moieties were designed, synthesized, and characterized using modern spectroscopic methods to yield 17 compounds (6a-6q) that were screened for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes in the search for 'lead' compounds for Alzheimer's disease treatment (AD). The compounds 6q, 6p, 6k, 6o, and 6l showed inhibitory capability against AChE and BChE, with IC50 values ranging from 11.73±0.49 to 27.36±0.29 µM for AChE and 21.83±0.39 to 39.43±0.44 µM for BChE, inhibiting both enzymes within a limited range. The SAR ascertained that the substitution of the aromatic moiety had a profound effect on the AChE and BChE inhibitory potential as compared to the aliphatic substitutions which were supported by the molecular docking studies. The drug-likeness of the most synthesized compounds was confirmed by in silico ADME investigations. These results were additionally supplemented by the molecular orbital analysis (HOMO-LUMO) and electrostatic potential maps got from DFT calculations. ESP maps expose that on all structures, there are two potential binding sites conquered by the most positive and most negative districts.

Synthesis of Cytospolide Analogues and Late-State Diversification Thereof.

The cytospolides are a novel group of fungal secondary metabolites first described in 2011. Although all 17 natural derivatives share the same C-14 polyketide backbone, they exhibit a fairly broad structural diversity regarding their oxygenation and acetylation pattern as well as macrolide structure, e.g., monocyclic nonanolide core or bicyclic ring systems with a bridging THF ring. In the present work, the prospects for an extension of the structural diversity of cytospolides have been investigated. On the basis of a previously established synthesis of cytospolide D, a modified route to a truncated analogue carrying an alkyne instead of the natural n-pentyl side chain has been developed. In a bioinspired approach the so-derived cytospolide D alkyne analogue has been further converted to bicyclic and THF ring containing derivatives with a different backbone architecture. Finally, Sonogashira couplings or Huisgen-Sharpless click reactions have been used for late-stage diversifications. Thus, a set of 15 novel and structurally diverse natural product derivatives has been synthesized in a highly efficient manner.

Regioselective dehydration of α-hydroxymethyl tetrahydrofurans using Burgess' reagent under microwave irradiation.

We here present a highly efficient and high yielding procedure for the preparation of 2-vinyl tetrahydrofurans starting from α-hydroxymethyl tetrahydrofurans. Best results for this dehydration were achieved using Burgess' reagent in dioxane under microwave irradiation. A range of functional groups as well as different cyclic and bicyclic frameworks were found to be compatible with the reaction conditions. The desired products were obtained within minutes in good to high yields and excellent regioselectivity.

Comparison of the trapezius and the adductor pollicis muscle as predictor of good intubating conditions: a randomized controlled trial.

BACKGROUND: Adequate muscle relaxation is important for ensuring optimal conditions for intubation. Although acceleromyography of the adductor pollicis muscle is commonly used to assess conditions for intubation, we hypothesized that acceleromyography of the trapezius is more indicative of optimal intubating conditions. The primary outcome was the difference between both measurement sites with regard to prediction of good or acceptable intubating conditions. METHODS: Neuromuscular blockade after injection of rocuronium 0.3 mg/kg IV was measured simultaneously with acceleromyography of the adductor pollicis muscle and the trapezius muscle in sixty female patients, American Society of Anesthesiologists physical status I to III, undergoing general anesthesia for gynecologic surgery. Exclusion criteria were: expected difficult tracheal intubation (e.g. history of difficult intubation, reduced mouth opening (< 2 cm) and/or Mallampati Score 4), increased risk of pulmonary aspiration (e.g. gastroesophageal reflux or delayed gastric emptying) allergies to drugs used during the study, pregnancy, neuromuscular diseases, medication with potential to influence neuromuscular function (e.g. furosemide, magnesium, cephalosporins) and hepatic or renal insufficiency (serum bilirubin >26 µmol/L, serum creatinine >90 µmol/l). Patients were randomized to 2 groups: group A (n = 30): endotracheal intubation after onset of the neuromuscular block at the adductor pollicis muscle. Group B (n = 30): endotracheal intubation after onset at the trapezius muscle. Intubating conditions were compared between both groups by means of a standardised score (the Copenhagen score) with Fisher's exact test. RESULTS: Onset of the block after rocuronium injection was observed at the adductor pollicis muscle compared to the trapezius with 2.8 (1.1) versus 2.5 (1.1) min (mean ± SD; P = 0.006). Intubating conditions were poor in 2 patients (7%) of group A, and in 1 patient (3%) of group T. They were acceptable (either excellent or good) in 28 patients (93%) in group A, and in 1 patient (97%) in group T (P = 0.82). CONCLUSIONS: Performing acceleromyography at the trapezius muscle reduced the time between injection of neuromuscular blocking agents and intubation by 18 s (11%). Thus, trapezius muscle acceleromyography is an acceptable alternative to adductor pollicis muscle acceleromyography in predicting acceptable intubating conditions, which allows for earlier indication of adequate intubating conditions. TRIAL REGISTRATION: ClinicalTrial.gov Identifier: NCT01849198 . Registered April 29, 2013.

Modular and Stereodivergent Approach to Unbranched 1,5,9,n-Polyenes: Total Synthesis of Chatenaytrienin-4.

An iterative strategy for the stereodivergent synthesis of unbranched 1,5,9,n-polyenes (and -polyynes) was investigated. Starting from a terminal alkyne the iteration cycle consists of a C3 extension (allylation), a chemoselective hydroboration, an alkyne reduction, and an oxidation of the associated alcohol with subsequent C1 homologation. Double bond geometry is controlled using stereoselective alkyne reductions, employing either the Lindlar hydrogenation protocol or an aluminum hydride reduction. In a model sequence it was demonstrated that the strategy is applicable to the synthesis of 1,5,9,n-polyenes with any possible double bond configuration accessible in equally high efficiency and selectivity. It is worth noting that our approach does not require any protecting group chemistry. Furthermore, using the same strategy, the first total synthesis of chatenaytrienin-4, the proposed unsaturated biosynthetic precursor of the bis-THF acetogenin membranacin, was examined. Thus, the all-cis 1,5,9-triene natural product was prepared in 15 steps from commercially available starting materials in 6% overall yield.

Monitoring recovery from rocuronium-induced neuromuscular block using acceleromyography at the trapezius versus the adductor pollicis muscle: an observational trial.

PURPOSE: Positioning for surgery can restrict access to the patient's hand, thereby limiting assessment of the response at the adductor pollicis muscle to ulnar nerve stimulation. We evaluated a novel site to assess neuromuscular block by stimulating the accessory nerve and measuring the acceleromyographic response at the trapezius muscle. METHODS: In this prospective non-blinded observational study, we assessed neuromuscular transmission in anesthetized adult female patients undergoing elective laparoscopic gynecological surgery. We performed the assessment by simultaneous recording acceleromyographic responses with the TOF-Watch(®) SX monitor at both the right adductor pollicis and left trapezius muscles. The neuromuscular block was achieved using rocuronium 0.3 mg·kg(-1), and the repeatability, time course, and limits of agreement (Bland-Altman) of responses were compared at the two recording sites. The primary endpoint was the 90% train-of-four (TOF) recovery time with other endpoints included the onset time of the block, maximum T1 depression, time to 25% T1 recovery, and recovery time course of the T1 response and TOF ratio. RESULTS: Thirty-six patients were enrolled with responses obtained from 27 subjects. The variability of baseline responses recorded at the trapezius muscle was larger than that recorded at the adductor pollicis muscle, as determined by their mean (SD) repeatability coefficients [twitch height T1, 6.1 (1.9)% and 4.2 (1.6)%, respectively; P = 0.001; TOF ratio, 6.2 (2.1)% and 4.3 (1.7)%, respectively; P = 0.001]. The recorded responses showed relatively narrow limits of agreement. The onset time of the block was 0.3 min earlier at the trapezius muscle than at the adductor pollicis muscle [2.3 (0.8) min and 2.6 (0.7) min, respectively; P = 0.007], with limits of agreement ranging from 1.6 min earlier to 1.0 min later. The time to 25% T1 recovery was 1.8 min earlier at the trapezius muscle than at the adductor pollicis muscle [18.2 (5.7) min and 20.0 (5.2) min, respectively; P = 0.039], with limits of agreement ranging from 11.1 min earlier to 7.5 min later. Additionally, the time to achieve 90% TOF ratio was 4.4 min earlier at the trapezius muscle than at the adductor pollicis muscle [32.6 (7.9) min and 37 (9.1) min, respectively; P = 0.004], with limits of agreement ranging from 18.4 min earlier to 9.7 min later. CONCLUSIONS: We conclude that recording evoked acceleromyographic responses at the trapezius muscle is an acceptable alternative when monitoring from the adductor pollicis muscle is compromised. Nevertheless, we caution that recording a 90% TOF response at the trapezius muscle may overestimate functional recovery from the neuromuscular blockade. This trial was registered at ClinicalTrials.gov identifier, NCT01849198.

Diastereodivergent Reverse Prenylation of Indole and Tryptophan Derivatives: Total Synthesis of Amauromine, Novoamauromine, and epi-Amauromine.

A regio- and stereoselective reverse prenylation of indole and tryptophan derivatives is presented. All four possible stereoisomers are accessible through this iridium-catalyzed reaction. The stereoselectivity is controlled by a chiral phosphoramidite ligand in combination with an achiral borane additive and can be switched by changing the nature of the borane. One enantiomer of the ligand is thus sufficient to prepare all possible isomers. The synthetic potential of this method was demonstrated by a short total synthesis of amauromine and its two natural diastereomers.

The direct oxidative diene cyclization and related reactions in natural product synthesis.

The direct oxidative cyclization of 1,5-dienes is a valuable synthetic method for the (dia)stereoselective preparation of substituted tetrahydrofurans. Closely related reactions start from 5,6-dihydroxy or 5-hydroxyalkenes to generate similar products in a mechanistically analogous manner. After a brief overview on the history of this group of transformations and a survey on mechanistic and stereochemical aspects, this review article provides a summary on applications in natural product synthesis. Moreover, current limitations and future directions in this area of chemistry are discussed.

Synthetic endeavors toward 2-nitro-4-alkylpyrroles in the context of the total synthesis of heronapyrrole C and preparation of a carboxylate natural product analogue.

The synthesis of 2-nitro-4-oligoprenyl-substituted pyrrole derivatives relevant to the heronapyrroles and related natural products was investigated. Among numerous approaches, nitration of a 3-farnesyl-substituted unprotected pyrrole using AcONO2 gave the best results, albeit still with unsatisfactory yield and regioselectivity. Therefore, the synthesis of (-)-heronapyrrole C acid, an analogue of the naturally occurring antibiotic heronapyrrole C carrying a bioisosteric carboxylate in place of the nitro group, was examined. In lieu of the unsatisfactory nitration, a regioselective acylation with Cl3CCOCl was carried out (>8:1 regioselectivity, in contrast to the 1:1.3 ratio for the nitration). The trichloromethyl ketone was converted to the desired acid in a haloform reaction at the final stage of the synthesis. Further key steps of the analogue synthesis involved a position- and stereoselective Corey-Noe-Lin dihydroxylation and an organocatalytic double Shi epoxidation. A biomimetic polyepoxide cyclization cascade established the bis-THF backbone. Thus, (-)-heronapyrrole C acid was synthesized in eight steps (14.5% overall yield) from commercially available starting materials.

Heronapyrrole D: A case of co-inspiration of natural product biosynthesis, total synthesis and biodiscovery.

The heronapyrroles A-C have first been isolated from a marine-derived Streptomyces sp. (CMB-0423) in 2010. Structurally, these natural products feature an unusual nitropyrrole system to which a partially oxidized farnesyl chain is attached. The varying degree of oxidation of the sesquiterpenyl subunit in heronapyrroles A-C provoked the hypothesis that there might exist other hitherto unidentified metabolites. On biosynthetic grounds a mono-tetrahydrofuran-diol named heronapyrrole D appeared a possible candidate. We here describe a short asymmetric synthesis of heronapyrrole D, its detection in cultivations of CMB-0423 and finally the evaluation of its antibacterial activity. We thus demonstrate that biosynthetic considerations and the joint effort of synthetic and natural product chemists can result in the identification of new members of a rare class of natural products.

Reduced plantar cutaneous sensation modifies gait dynamics, lower-limb kinematics and muscle activity during walking.

Peripheral neuropathy is the most common long-term complication in diabetes and is involved in changes in diabetic gait and posture. The regression of nerve function leads to various deficits in the sensory and motor systems, impairing afferent and efferent pathways in the lower extremities. This study aimed to examine how reduced plantar-afferent feedback impacts the gait pattern. Cutaneous sensation in the soles of both feet was experimentally reduced by means of intradermal injections of an anaesthetic solution, without affecting foot proprioception or muscles. Ten subjects performed level walking at a controlled velocity before and after plantar anaesthesia. Muscle activity of five leg-muscles, co-contraction ratios for the knee and ankle joint, ground reaction forces (GRF), spatiotemporal characteristics, joint angles and moments of the hip, knee and ankle were analysed. The intervention significantly lowered plantar sensation, reducing it to the level of sensory neuropathy. Spatiotemporal gait characteristics remained unchanged. The ankle joint was more dorsiflexed which coincided with increased tibialis anterior and decreased gastrocnemius medialis muscle activity during foot flat to mid-stance. In addition, the knee joint was more flexed accompanied by increased biceps femoris activity and higher internal knee-extension moment. With regard to gait dynamics, a delay of the first peak of the vertical GRF was observed. Increased soleus and tibialis anterior muscle activity were found during the end of stance. Short-term loss of plantar sensation affects lower-limb kinematics and gait dynamics, particularly during the first half of stance, and contributes to modified muscle-activation patterns during locomotion.

Hepatic and HSC-specific sorafenib effects in rats with established secondary biliary cirrhosis.

Portal hypertension in cirrhosis depends on increased intrahepatic vascular resistance, which is explained by fibrosis and intrahepatic hyperresponsiveness to vasoconstrictors. Both are caused by activation and proliferation of hepatic stellate cells (HSCs). Portal hypertension of cirrhotic rats can be reduced by the multikinase inhibitor sorafenib, due to a reduction of intrahepatic vascular resistance. Therefore, the hepatic effects of sorafenib require further understanding. Here, we investigated hepatic and HSC-specific sorafenib effects in cirrhotic rats. Animal models of bile duct ligation-induced secondary biliary cirrhosis in rats were studied. The rats were treated with sorafenib (60 mg/kg/day) for 1 week, starting after established cirrhosis. Histological evaluation was carried out using hemalaun and eosin (HE) staining. Apoptosis was studied by PARP cleavage, colorimetric caspase-3 assay, and electrophoretic DNA detection. HSC activation was studied by hepatic Sirius red and immunohistochemical αSMA (α-smooth muscle actin) staining, and by in vitro experiments with culture-activated primary HSCs. Biochemical serum parameters suggested the occurrence of sorafenib-induced liver damage. HE staining revealed histological changes in livers of sham-operated and bile duct-ligated (BDL) rats in response to sorafenib, which were different in both groups. In BDL rats and isolated HSCs, the treatment with sorafenib reduced hepatic αSMA and procollagen-1α mRNA expression. As shown by immunohistochemical staining, perisinusoidal αSMA expression was reduced by sorafenib in BDL rats. This was associated with reduced perisinusoidal deposition of extracellular matrix, as revealed by Sirius red staining. Although no change in PARP cleavage and only a minor increase in hepatic caspase-3 activity were detected in BDL rats in response to sorafenib, livers of sorafenib-treated BDL rats contained small DNA fragments, which were not observed in untreated BDL rats. In conclusion, sorafenib treatment reduces the number of activated HSCs in cirrhotic livers. This leads to the decrease in intrahepatic vascular resistance, but also to liver damage in the dosage we used. Therefore, any translation to portal hypertensive patients who may profit from sorafenib should be done with particular care.

Synthesis of ß-functionalized temoporfin derivatives for an application in photodynamic therapy.

The synthesis of novel ß-functionalized derivatives of the clinically used photosensitizer Temoporfin has been achieved by nucleophilic addition reactions to a corresponding diketo chlorin. The ß-substituted dihydroxychlorin products exhibit a strong absorption in the red spectral region, a high singlet oxygen quantum yield, and were found to be highly effective in in vitro assays against HT-29 tumor cells.

Light-Driven Waste-To-Value Upcycling: Bio-Based Polyols and Polyurethanes from the Photo-Oxygenation of Cardanols.

The upcycling of waste biomass into valuable materials by resource-efficient chemical transformations is a prime objective for sustainable chemistry. This approach is demonstrated in a straightforward light-driven synthesis of polyols and polyurethane foams from the multi-ton waste products of cashew nut processing. The photo-oxygenation of cardanol from nutshell oil results in the formation of synthetically versatile hydroperoxides. The choice of the workup method (i. e., reduction, hydrogenation, epoxidation) enables access to a diverse range of alcohols with tunable alkene and OH functions. Condensation with isocyanates to give rigid polyurethane foams provides a resource-efficient waste-to-value chain that benefits from the availability of cardanol and installation of OH groups from aerial O2 .

Synthesis of Dideoxy-octonic Acid and Cyclic and Acyclic Derivatives Thereof.

Oxidative cleavage of N-acetyl-neuraminic acid (Neu5Ac, 1) leads to the open chain octonic acid (ADOA, 2), which under various conditions is transformed into an acyclic acid or ester or into a six- or five-membered octonic acid lactone and lactam, respectively. All reactions proceed with high selectivity and in good yields. Strikingly, a simple switch of reaction conditions from basic to acidic catalysis leads to a complete switch in regioselectivity during a crucial cyclization step.

Nucleophilic Thioglycosylation of Pentafluorophenyl-Substituted Porphyrinoids: Synthesis of Glycosylated Calix[n]phyrin and [28]Hexaphyrin Systems.

The use of carbohydrate thiolates for facile, high-yielding, regio- and stereoselective nucleophilic substitution reactions of complex pentafluorophenyl-substituted porphyrinoids is reported. The title reaction has successfully been applied to calix[4]phyrin, calix[6]phyrin, and [28]hexaphyrin substrates. The novel glycoporphyrinoid products with their extraordinary structures and unique photophysical properties are soluble in aqueous solutions and can serve as platforms for applications in biomedicine, catalysis, coordination, or redox chemistry.

Real-time compensation method for robust polarimetric determination of glucose in turbid media.

Polarimetric determination of glucose is known to be strongly affected by scattering in turbid media. Other effects like fluctuations of light source emission and sample absorption also deteriorate glucose predictability. This work presents a measurement setup using a real-time data processing method to address these problems. The approach uses the frequency-dependent intensity components created when the polarization of the incident light is periodically modulated by a Faraday rotator. The efficacy of the proposed method was verified experimentally for a glucose range of 0 - 500 mg/dl. It was shown that the approach reduces the prediction errors in slightly turbid media from 35.7 mg/dl down to 1.17 mg/dl. In a similar way, the glucose predictability for fluctuating light source emission was improved from ±16.16 mg/dl to ±1 mg/dl and for varying sample absorbance from ±15.69 mg/dl to ±1.23 mg/dl, respectively. Therefore, considerable improvement of robustness and reproducibility of glucose determination was demonstrated.

Broadband polarimetric glucose determination in protein containing media using characteristic optical rotatory dispersion.

One of the major challenges during polarimetric determination of glucose concentration is the spectral superposition with other optically active molecules, especially proteins like albumin. Since each of those substances has a characteristic optical rotatory dispersion (ORD), we developed a broadband polarimeter setup to distinguish between glucose and albumin. A partial least squares (PLS) regression with 5 components was applied to the polarimeter signal in the wavelength range of 380 - 680 nm . To verify the efficacy of the proposed method, different glucose levels of 0 - 500 mg/dl were spiked with varying albumin concentrations up to 1000 mg/dl . A standard error of prediction of ± 16.0 mg/dl was achieved compared to ± 128.3 mg/dl using a two-wavelength system with 532 nm and 635 nm under the same conditions.