The formation of two different types of radicals in phosphonicacid esters (O-dimethyl-[1-hy- droxy- 2 , 2 , 2 -trichloroethyl] -phosphonate, trichlorphon; 0 , 0 -dimethyl- [ 1 -hydroxy-l-methylethyl] -phos- phonate) Mowing reaction with OH radicals is shown by ESR Hfs. Coupling constants for H, P and Cl and g-values are given and discussed. The results in liquid phase (oxidation by OH) are compared with results on radiation-induced radicals in solid trichlorphon.
The main peaks for the LINE and the SQUARE in the solid-state NMR spectra are located at 21 ppm and 17 ppm, as shown in Figure 4.20. In the case of the LINE, this observation is somehow contrary to the broad peak observed in the 1 H MAS NMR, as mentioned above. This might be explained by the larger homonuclear dipolar coupling which broadens the 1 H signal, while the higher ordered structure shows a narrow line in the hetero nuclei spectra. With respect to the results obtained in section 4.2 the PA of the LINE has a strong homonuclear dipolar coupling. In addition, both 31 P MAS NMR spectra of the LINE and SQUARE show some additional peaks. The small peak at 15 ppm in the LINE spectrum most probably corresponds to the anhydride (POP). This assumption is supported by various 31 P MAS NMR spectra of phosphonicacid and anhydride containing samples [LEE 07a, STEININGER 07]. Nevertheless, this group of chemical compounds provides a new possibility to assign this signal. The HEXAGON, as an example, shows, besides the major peak at 18 ppm a shoulder at 23 ppm which could be a structural impurity of 5%, which is the same amount found in the VT 1 H MAS NMR spectra in subsection 4.3.2. The assumption of different PA sites is supported by the 31 P MAS NMR spectra of the HEXAGON when stored under 100% RH. Here, the resolution increases due to higher mobility resulting in a splitting of the broad signal, see Figure 4.21. Additionally, it is observed, that the center of the phosphorous chemical shift under wet conditions is located at smaller ppm values. This, however, suggests that the phosphorous with higher chemical shift values represent the PAs which are not interacting with water.
Conventional m ethods for anhydride prepara tion were used for the synthesis of the title com pounds. These included the condensation of phos phonic acid dichloride and phosphonicacid dimethyl ester (R = Me), hydrolysis of phosphonicacid dichlorides (R = E t), and reaction of a phos phonic acid with its dichloride (R = /-Pr, r-Bu and Ph). The yields were generally quite acceptable, and elem ental analyses gave satisfactory data. However, according to spectroscopic data the pu rity of the products is poor in most cases (for de tails see the Exp. Part below and references [6-8]).
50 B. Laber et al. ■ PA L Inhibition by Phosphonic A n alogu e o f Phenylalanine
centration of l-A O P P in a tissue and reduce its effi ciency as an inhibitor. F urtherm ore, other biosynthe tic pathways, such as ethylene synthesis , are af fected by these high concentrations of l-A O P P . In addition, tyrosine decarboxylases from certain plants are strongly inhibited by l-A O P P (B. E. Ellis, p e r sonal com m unication). Thus, the specificity of l- A O PP for PA L must be interpreted with caution, and the search for new inhibitors of PA L is w orth while. Inhibition of PA L by cinnamic acid deriva tives and related com pounds has been investigated more recently , but the K t values even of the most active com pounds were in the same range as the K m values, and little inform ation was given on the specificity of the com pounds for PAL in vivo. In this com m unication, we wish to report that, of the many putative inhibitors which we screened over the years, the phosphonic analogue of L-phenylalanine, (i?)-(l- am ino-2-phenylethyl)phosphonicacid (A P E P ), is another promising inhibitor of PA L, both in vitro and in vivo.
The phosphonate anions may function as linkers connecting inorganic oxide and organic groups giving a great variety of structure types: 1D chains, 2D layers, 3D network, and 3D network with channels.  Due to the tetrahedral nature of the phosphonicacid group and the presence of two protons and three oxygens, the obtained compounds differed greatly from the carboxylic analogues. No structure solution of these compounds is possible by X-ray or neutron diffraction techniques since the cross-linked compounds form particles that precipitate rapidly into nanoparticles that exhibit only short range order. Therefore, they must be understood on the basis of modeling and indirect data from EM, NMR, and additional spectroscopic and textural studies.  One refers to organic-inorganic hybrid materials or metal phosphonate open-framework materials instead of MOFs when porous compounds are synthesized using phosphonicacid based linkers. [132, 133]
1 , 2 -diphosphonic acid ( vide infra), the 31P chemical shifts for the sodium salts of H E D P do not show a simple trend as protons are subsequently replaced by sodium ions. (Indeed, from exam ination of the spec tra in the stack plot of Fig. 1 and comparison of their linewidths, it seems likely that the two resonances cross over betw een l a and l c .) There are probably a num ber of reasons for the lack of a simple trend including: 1 ) the effect of the hydroxyl group; 2 ) a more com plicated hydrogen bonding structure result ing from the closer proximity of the phosphonicacid groups; and 3 ) chemical shift changes due to crystal- lographic distortions.
Nucleophilic phosphanylation of orf/zo-fluorophenylacetic acid or orf/jofluorobenzylamine with PhPH2 using KOfBu as the base affords the hydrophilic tertiary phosphanes 3 and 4a with terminal CH2-COOH and CH2-NH2 substituents. The corresponding secondary phosphane li gands 2 or 5 may be obtained by Pd-catalyzed P-C coupling of orr/ 20-iodophenylacetic acid with PhPH2 or selective nucleophilic phosphanylation of orf/jo-fluorophenylacetic acid. Novel phosphonatomethyl derivatives 7a, 7b of triphenylphosphane have been obtained in a two sta ge synthesis using orf/zo-iodobenzylchloride or w^ta-iodobenzylbromide as starting materials. Arbusov reaction with P(OEt)3 and Pd-catalyzed P-C coupling reactions with Ph2PH gave the esters 7a, 7b. Purification of 7a was achieved via its BH 3 adduct 8a. Deprotection, hydrolysis and neutralisation with NaOH affords the water soluble sodium salts 9a,9b. a-Hydroxy and a-benzylamino derivatives 12 and 14 of orr/zo-diphenylphosphanobenzyl phosphonate (e.g. 7a)
The biosynthesis of carboxylic acids including fatty acids from biomass is central in envis- aged biorefinery concepts. The productivities are often, however, low due to product toxicity that hamper whole-cell biocatalyst performance. Here, we have investigated factors that influence the tolerance of Escherichia coli to medium chain carboxylic acid (i.e., n-hepta- noic acid)-induced stress. The metabolic and genomic responses of E. coli BL21(DE3) and MG1655 grown in the presence of n-heptanoic acid indicated that the GadA/B-based glu- tamic acid-dependent acid resistance (GDAR) system might be critical for cellular toler- ance. The GDAR system, which is responsible for scavenging intracellular protons by catalyzing decarboxylation of glutamic acid, was inactive in E. coli BL21(DE3). Activation of the GDAR system in this strain by overexpressing the rcsB and dsrA genes, of which the gene products are involved in the activation of GadE and RpoS, respectively, resulted in acid tolerance not only to HCl but also to n-heptanoic acid. Furthermore, activation of the GDAR system allowed the recombinant E. coli BL21(DE3) expressing the alcohol dehydro- genase of Micrococcus luteus and the Baeyer-Villiger monooxygenase of Pseudomonas
(1 5)-(+)-Fenchone is sulfonated by S 0 3 or H2S 0 4/acetic anhydride in the bridgehead methyl group. This could be confirmed by NMR techniques (INADEQUATE). The fenchonesulfonic acid obtained is converted (SOCl2/NH3) to the cyclic fenchonesulfonimide, which can be oxidized to the corresponding oxaziridine, in close analogy to 10-camphorsul- fonimide. Improved procedures for this reaction sequences are given. During the treatment of the sulfonic acid with thionyl chloride, a byproduct with a rearranged bicyclic skeleton is observed whose structure has been determined by ozonolytic degradation and NMR tech niques. A possible mechanism for this rearrangement is suggested, based on MNDO calcu lations of the intermediate carbocations. The fenchonesulfonyloxaziridine oxidizes sulfides to chiral sulfoxides with appreciable enantiomeric excess, but very low reaction rate. A com parison with camphor-derived oxaziridines having similar steric requirements is made.
In this context it has been proposed that the human genetic profile was originally established on a n-6 to n-3 PUFA ratio of approximately 1:1 as found in “ancient” diets, whereas today’s Western diet has been estimated to provide n-6 to n-3 PUFAs in a ratio of 15:1–20:1. It has been hypothesized that this may contribute to many serious health issues typically found in Western societies, including CRC. However, previous in vitro observations have led to some uncertainty regarding differential roles of n-3 and n-6 PUFAs in CRC cells. While the majority of investigations conducted in this field addressed neither the effects of n-6 PUFAs nor the impact of a balanced n-6 to n-3 PUFA ratio, several other studies reported n-3 and n-6 PUFAs to exert anti-cancerous effects in vitro. Hence, it was the aim of the present study to investigate the impact of n-3 PUFA docosahexaenoic acid (DHA) and n-6 PUFA AA and their combination on CRC cell line LS 174T in vitro.
was passed through a preconditioned (with m eth anol, water and 0.2 m acetic acid) Sep-Pak C18 cartridge (Millipore W aters, U.S.A.).
The cartridge was washed with 0.2 m acetic acid and 10% MeOH; ABA was eluted with 5 ml of M eC )H -0.2M acetic acid (3:2, v/v). The eluate was evaporated at 35 °C with a stream of N 2, the residue was dissolved in 500 (il M eO H and used for ABA quantification by high perform ance thin layer chrom atography (H PTLC) and scanning densitom etry using TLC Scanner II by Cam ag (Switzerland).
80 g 5-brom olevulinic acid methyl ester (2)  were dissolved in 300 ml dimethyl form amide and 80 g potassium phthalim ide were slowly added under stirring. The solution was stirred for 1 h at room tem perature, filtered and worked up with
discussed . According to the “preferential exclusion hypothesis”, established for protein stabilization, solutes are preferentially excluded from the surface resulting in the formation of a stabilizing solvent layer [17, 178-179]. However, it is questionable if this hypothesis can be adapted to nucleic acid nanoparticles, as the relatively high amounts of cryoprotectants required point to a nonspecific bulk stabilization [17, 178-179]. Based on the “glass formation or vitrification hypothesis”, nucleic acid nanoparticles are entrapped in the amorphous gassy matrix when the sample is cooled below the glass transition temperature (Tg`) limiting particle mobility and thus, preventing particle aggregation [17, 178]. As some sugars were able to preserve particle size at temperatures well above Tg` vitrification cannot be the only stabilization mechanism . The “particle isolation hypothesis” states that particles have to be sufficiently separated in the freeze-concentrate in order to inhibit particle aggregation, which is observed above a critical excipient to complex ratio . However, these three mechanisms are not suitable to solely explain the stabilization of nucleic acid nanoparticles during freezing. Thus, the influence of freezing on nucleic acid nanoparticles and underlying stabilization mechanisms during freezing will be addressed in detail in Chapter 6.
First, selective reduction of the carbonic acid to a prim ary alcohol with diborane or borane-dim ethyl- sulfide complex , and second, oxidation of the alcohol to an aldehyde function with pyridinium dichrom ate  or other approved reagents (Fig. 4). The reduction of 1 to the alcohol 6 was accomplished easily in 65% yield but the oxidation of 6 failed. T reatm ent of 6 with pyridinium dichrom ate yielded only overoxidized product 1 whereas 6 rem ained un changed by treatm ent with pyridiniumchlorochro- m ate . O th er reagents were not tried with regard to the acid lability of the protective groups.
The direct electrocatalytic valorisation of platform chemicals without prior separation from crude fermentation broth pre- sents a valuable approach to minimize the number of required unit operations and energy demand. Focusing on the reduction of itaconic acid (IA) as a case study, an e ﬃcient chemo-catalytic hydrogenation of neat IA over Ru/C or RANEY® nickel required at least 70 °C and 10 bar of hydrogen pressure facilitating 75% yield of methylsuccinic acid (MS). However, the presence of various salts as well as glucose prohibited a chemo-catalytic valorisation of an IA fermentation broth. In the case of RANEY® nickel a distinct catalyst leaching occurred. In contrast, we were able to transform IA into methylsuccinic acid (MS) over various electrodes at ambient temperature and pressure. Pb and Ni facilitated the highest activity in a separated single electrolysis cell. Pb showed under slightly di ﬀerent conditions the highest activity with a maximum yield of MS of 98% at room tempera- ture, −1.41 V vs. SHE in an aqueous, acidic medium. The applied voltage has a distinct impact on the conversion and faradaic eﬃciency with an increasing faradaic eﬃciency at lower potentials but increasing conversion for higher potentials further rising until mass transfer limitation becomes rate limit- ing. Interestingly, the conversion of IA only slightly declined for an IA fermentation broth instead of neat IA in a diluted sulfuric acid environment confirming the potential of this strategy. Future studies will elaborate on further transformations and substrates. Overall, the electrocatalytic valorisation of a crude biotechnological product stream reduces not only energy demand and unit operations but presents a promising approach to introduce renewable electrical energy in biomass utilization.
hand, delivery of nucleic acids using delivery vehicles such as liposomes, polymers and nanoparticles has been met with considerable success [18-20]. 1,2-dioleoyl-3- trimethylammonium-propane (DOTAP), 1,2-di-O-octadecenyl-3-trimethylammonium propane (DOTMA), (1-[2-(9-(Z)-octadecenoyloxy)ethyl] -2-(8-(Z)-heptadecenyl) -3 (hydroxyethyl) imidazolinium chloride (DOTIM), N-methyl-4(dioleyl)methylpyridiniumchloride (SAINT), 1,2-dimyristyloxy-propyl-3-dimethyl-hydroxy ethyl ammonium bromide (DMRIE), 1,2-di- (9Z-octadecenoyl)-sn-glycero-3- [(N- (5-amino-1-carboxypentyl) iminodiacetic acid) succinyl (DOGS), and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) are the most frequently used lipids for delivery of nucleic acids [21, 22]. Among polymers, polyethylenimine (PEI; linear and branched) of various molecular weights, poly-L-lysine (PLL), chitosan, polyamidoamine (PAMAM) are widely used [23, 24]. Poly (lactic-co-glycolic acid) (PLGA) and silica particles have been proven to be indispensable for formulation of nanoparticles for gene delivery . Several therapies which are under clinical evaluation are based upon one of these vectors .
* Correspondence: firstname.lastname@example.org; Tel.: +49-201-723-84579; Fax: +49-201-723-5974 Received: 11 October 2019; Accepted: 7 December 2019; Published: 11 December 2019 Abstract: Farber disease is a rare lysosomal storage disorder resulting from acid ceramidase deficiency and subsequent ceramide accumulation. No treatments for Farber disease are clinically available, and affected patients have a severely shortened lifespan. We have recently reported a novel acid ceramidase deficiency model that mirrors the human disease closely. Acid sphingomyelinase is the enzyme that generates ceramide upstream of acid ceramidase in the lysosomes. Using our acid ceramidase deficiency model, we tested if acid sphingomyelinase could be a potential novel therapeutic target for the treatment of Farber disease. A number of functional acid sphingomyelinase inhibitors are clinically available and have been used for decades to treat major depression. Using these as a therapeutic for Farber disease, thus, has the potential to improve central nervous symptoms of the disease as well, something all other treatment options for Farber disease can’t achieve so far. As a proof-of-concept study, we first cross-bred acid ceramidase deficient mice with acid sphingomyelinase deficient mice in order to prevent ceramide accumulation. Double-deficient mice had reduced ceramide accumulation, fewer disease manifestations, and prolonged survival. We next targeted acid sphingomyelinase pharmacologically, to test if these findings would translate to a setting with clinical applicability. Surprisingly, the treatment of acid ceramidase deficient mice with the acid sphingomyelinase inhibitor amitriptyline was toxic to acid ceramidase deficient mice and killed them within a few days of treatment. In conclusion, our study provides the first proof-of-concept that acid sphingomyelinase could be a potential new therapeutic target for Farber disease to reduce disease manifestations and prolong survival. However, we also identified previously unknown toxicity of the functional acid sphingomyelinase inhibitor amitriptyline in the context of Farber disease, strongly cautioning against the use of this substance class for Farber disease patients.
Most acid sulfate soils are of Holocene age and were mostly formed during and after the early Holocene sea level rise, which induced the formation of thick and extensive pyritic sediments in many coastal plains of the world (Pons et al., 1982). After the sea level rise leveled off around 5000 yrs. BP, sediments with lower pyrite content accumulated in areas with large sedimentation rates and fast coastal accretion (Pons et al., 1982). Under lower sedimentation rates, highly pyritic peats could be deposited. The interplay of sedimentation, sea level rise and paleo-relief was a governing factor for acid sulfate soil formation during the Holocene. These factors controlled the extent and persistence of the intertidal zones and tidal creeks, which were essential for pyrite accumulation. In a general view, the formation of these soils is controlled by changes in sea level, sedimentation rate, paleo-relief, local tectonics, vegetation and the chemical limiting factors for the formation of sulfides as described above. This variety of controls has to be considered in detail to predict acid sulfate soil distribution.