Asymmetric Transfer Hydrogenation as a Key Step in the Synthesis of the Phosphonic Acid Analogs of Aminocarboxylic Acids.

α-Aminophosphonic acids have a remarkably broad bioactivity spectrum. They can function as highly efficient transition state mimics for a variety of hydrolytic and angiotensin-converting enzymes, which makes them interesting target structures for synthetic chemists. In particular, the phosphonic acid analogs to α-aminocarboxylic acids (Pa AAs) are potent enzyme inhibitors, but many of them are only available by chiral or enzymatic resolution; sometimes only one enantiomer is accessible, and several have never been prepared in enantiopure form at all. Today, a variety of methods to access enantiopure α-aminophosphonic acids is known but none of the reported approaches can be generally applied for the synthesis of Pa AAs. Here we show that the phosphonic acid analogs of many (proteinogenic) α-amino acids become accessible by the catalytic, stereoselective asymmetric transfer hydrogenation (ATH) of α-oxo-phosphonates. The highly enantioenriched (enantiomeric excess (ee) ≥ 98 %) α-hydroxyphosphonates obtained are important pharmaceutical building blocks in themselves and could be easily converted to α-aminophosphonic acids in most studied cases. Even stereoselectively deuterated analogs became easily accessible from the same α-oxo-phosphonates using deuterated formic acid (DCO2 H).

(R)-[18F]NEBIFQUINIDE: A promising new PET tracer for TSPO imaging.

Positron emission tomography (PET) imaging of the 18 kDa translocator protein (TSPO), has a high diagnostic potential in neurodegenerative disorders and cancer. However, TSPO is considered a challenge for molecular imaging due to the poor availability of suitable radiotracers with adequate pharmacokinetic properties. Here, we describe the development of a radiofluorinated pyridinyl isoquinoline analogue of the established TSPO PET tracer (R)-[11C]PK11195 with improved binding properties in all known human TSPO phenotypes. We conducted a complete preclinical evaluation using in vitro, in vivo and ex vivo methods to assess the performance of this novel radiotracer and observed high specific binding of the radiotracer to TSPO, as well as high metabolic stability. Therefore, we propose this radiolabeled compound for further evaluation in animal models as well as in clinical trials.

Synthesis and in vitro evaluation of new translocator protein ligands designed for positron emission tomography.

AIM: Dysregulated levels of the translocator protein TSPO 18 KDa have been reported in several disorders, particularly neurodegenerative diseases. This makes TSPO an interesting target for the development of diagnostic biomarkers. Even though several radioligands have already been developed for in vivo TSPO imaging, the ideal TSPO radiotracer has still not been found. RESULTS: Here, we report the chemical synthesis of a set of new TSPO ligands designed for future application in positron emission tomography, together with the determination of their biological activity and applied 11C-labeling strategy. CONCLUSION: The lead compound of our series, (R)-[11C]Me@NEBIQUINIDE, showed very promising results and is therefore proposed to be further evaluated under in vivo settings.

An Oxidative Pathway for Microbial Utilization of Methylphosphonic Acid as a Phosphate Source.

Methylphosphonic acid is synthesized by marine bacteria and is a prominent component of dissolved organic phosphorus. Consequently, methylphosphonic acid also serves as a source of inorganic phosphate (Pi) for marine bacteria that are starved of this nutrient. Conversion of methylphosphonic acid into Pi is currently only known to occur through the carbon-phosphorus lyase pathway, yielding methane as a byproduct. In this work, we describe an oxidative pathway for the catabolism of methylphosphonic acid in Gimesia maris DSM8797. G. maris can use methylphosphonic acid as Pi sources despite lacking a phn operon encoding a carbon-phosphorus lyase pathway. Instead, the genome contains a locus encoding homologues of the non-heme Fe(II) dependent oxygenases HF130PhnY* and HF130PhnZ, which were previously shown to convert 2-aminoethylphosphonic acid into glycine and Pi. GmPhnY* and GmPhnZ1 were produced in E. coli and purified for characterization in vitro. The substrate specificities of the enzymes were evaluated with a panel of synthetic phosphonates. Via 31P NMR spectroscopy, it is demonstrated that the GmPhnY* converts methylphosphonic acid to hydroxymethylphosphonic acid, which in turn is oxidized by GmPhnZ1 to produce formic acid and Pi. In contrast, 2-aminoethylphosphonic acid is not a substrate for GmPhnY* and is therefore not a substrate for this pathway. These results thus reveal a new metabolic fate for methylphosphonic acid.

Preparation of Phosphonic Acid Analogues of Proline and Proline Analogues and Their Biological Evaluation as δ1-Pyrroline-5-carboxylate Reductase Inhibitors.

Racemic 1-hydroxy-3-butenyl-, 3-chloro-1-hydroxypropyl-, and 3-bromo-1-hydroxypropylphosphonate and the corresponding (S)-enantiomers obtained by lipase-catalyzed resolution of the respective racemic chloroacetates were subjected to functional group manipulations. These comprised ozonolysis, Mitsunobu reactions with hydrazoic acid and N-hydroxyphthalimide, alkylation of hydrazine derivative, removal of phthaloyl group followed by intramolecular substitution, and global deprotection to deliver the racemates and (R)-enantiomers (ee 92-99% by chiral high-performance liquid chromatography) of pyrrolidin-2-yl-, oxazolidin-3-yl-, oxazolidin-5-yl-, pyrazolidin-3-yl-, and 1,2-oxazinan-3-ylphosphonic acids. These phosphonic acids were evaluated as analogues of proline and proline analogues for the ability to inhibit γ-glutamyl kinase, δ1-pyrroline-5-carboxylate synthetase, and δ1-pyrroline-5-carboxylate reductase. Only the latter enzyme was inhibited by two of them at concentrations exceeding 1 mM.

Safe Return to Driving After Volar Plating of Distal Radius Fractures.

PURPOSE: A major concern for patients following distal radius fracture fixation is when they can resume driving. This decision has medical, legal, and safety considerations, but there are no evidence-based guidelines to assist the surgeon. The goal of this study was to observe when patients are capable of safely resuming driving following surgical fixation of the distal radius. METHODS: Patients undergoing volar plating of a distal radius fracture were prospectively enrolled. At approximately 2 and 4 weeks after surgery, patients were administered a driving examination on a closed course and given a subjective questionnaire including visual analog scale scores. All basic functions of vehicle operation were evaluated. Successful completion indicated they would pass a driving evaluation. RESULTS: Twenty-three patients were enrolled. Sixteen (69.5%) passed their first attempt (average of 18.4 days from surgery), another 4 (17.4%) passed their second attempt (31.3 days from surgery), and 3 did not complete the second examination. Patients who failed relied too much on their nonsurgical hand, were not able to control the steering wheel with 2 hands, and reported pain and insecurity when using the operative hand. Of those who passed the second attempt, the first failure was universally attributed to pain. Fifteen patients reported a return to independent driving prior to the first examination (average, 11.3 days). Of the 7 who failed, 6 reported they could control the car in an emergency, and 2 reported they would not feel safe with daily driving. Maximum pain while driving on the visual analog scale was 2.4 of 10 among those who failed compared with 1.3 among those who passed. CONCLUSIONS: Most patients could safely return to driving within 3 weeks of surgery. Pain was the primary limiting factor affecting driving ability. Safe return to driving may be warranted within 3 weeks of distal radius volar plate fixation in some patients. Persistent pain is likely the most important obstacle to a safe return to driving. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic IV.

The development of a low-cost three-dimensional printed shoulder, arm, and hand prostheses for children.

BACKGROUND AND AIM: The prosthetic options for higher level amputees are limited and costly. Advancements in computer-aided design programs and three-dimensional printing offer the possibility of designing and manufacturing transitional prostheses at very low cost. The aim of this project was to describe an inexpensive three-dimensional printed mechanical shoulder prosthesis to assist a pre-selected subject in performing bi-manual activities. TECHNIQUE: The main function of the body-powered, manually adjusted three-dimensional printed shoulder prosthesis is to provide a cost-effective, highly customized transitional device to individuals with congenital or acquired forequarter amputations. DISCUSSION: After testing the prototype on a young research participant, a partial correction of the patient's spinal deviation was noted due to the counterweight of the device. The patient's family also reported improved balance and performance of some bimanual activities after 2 weeks of using the device. Limitations of the design include low grip strength and low durability. Clinical relevance The prosthetic options for higher level amputees are limited and costly. The low-cost three-dimensional printed shoulder prosthesis described in this study can be used as a transitional device in preparation for a more sophisticated shoulder prosthesis.