Computational, Synthetic, and Spectroscopic Investigations of PTA and Derivatives Towards Drug Development and Rare Earth Metal Extraction from Aqueous Media

The synthesis of novel upper-rim PTA-amides, where PTA is 1,3,5-triaza-7-phosphaadamantane, was attempted through several synthetic routes including those utilizing both amine and carboxylic acid-based PTA starting materials. Nitrogen-carbon amide bond formation was attempted between upper-rim PTA-enamines and nitrogen-protected amino acids with the coupling agent 3-[bis(dimethylamino)methyliumyl]-3H-benzotriazol-1-oxide (HBTU) and diisopropylethylamine (DIPEA). The upper-rim benzylamide of PTA was prepared by nucleophilic attack of methyl-1,3,5-triaza-7-phosphatricyclo[3.3.1.1]-decane-6-carboxylate (PTA-CO2Me) by benzylamine, facilitated by sodium methoxide in THF. Hydrochloride salts of butylamine and benzylamine as well as methyl ester-protected amino acids histidine and glycine were coupled to lithium 1,3,5-triaza-7-phosphaadamantane-6-carboxylate (PTA-CO2Li) with the assistance of HBTU and DIPEA in DMF. These upper-rim PTA amides were characterized with both NMR spectroscopy and Fourier-Transform Infrared Spectroscopy (FT-IR) and selectivity as high as 100% was observed when the reaction was conducted with alkyl and aryl substrates.The oxidation of upper-rim PTA enamines was optimized and the isomerization kinetics of one derivative PTA=C[C5H2(OMe)3]NH2 were investigated with time-resolved 31P{1H} NMR at variable temperatures. Equilibrium constants of 0.871, 0.866, and 0.897 were determined for the isomerization at 25 ºC, 35 ºC, and 45 ºC, respectively. Rate constants for conversion of the E isomer to the Z isomer were found to be 1.42 x 10-2, 2.52 x 10-2, and 5.27 x 10-2 at the same temperatures as well, respectively.The coordination modes of PTA were investigated with Density Functional Theory (DFT) to elucidate the location of electron density around the nucleophilic phosphorus and nitrogen atoms of the phosphine. It was found that most of the electron density of the Highest Occupied Molecular Orbital (HOMO) is centered around a nitrogen atom, which potentially explains the observed borane substitution behavior that has been referenced in previous publications, at least in part. The coordination modes of several metal-PTA and metal-O=PTA complexes were also investigated with nickel and Ln3+, respectively, where Ln3+ is La, Ce, Eu, Sm, and Yb. Characterization with 31P{1H} NMR spectroscopy (solid state and solution state), single-crystal X-ray diffraction, and FT-IR suggests that the nickel-PTA complexes are phosphorus-bound, as opposed to nitrogen-bound as was previously eluded to in the literature. Characterization of lanthanide complexes with O=PTA reveal oxygen-coordination is the exclusive coordination mode between the phosphine oxide and the metals.The pH-dependent precipitation of lanthanides from aqueous media with the use of lithium 1,3,5-triaza-7-phosphaadamantane-6-carboxylate (PTA-CO2Li) was investigated and optimized. The pKa of [PTA-CO2-][H+] was experimentally determined to be 6.1 ± 0.2 through an NMR titration, and relative energy calculations comparing the different isomers of the ligand suggest that protonation of the 3-nitrogen yields the most stable structure and the carboxylic acid is the least stable. The pKa of [PTA-(CO2)2-][H+] was experimentally determined to be 6.09 ± 0.52 through an NMR titration as well. Reaction conditions required to precipitate lanthanides (La3+, Gd3+, and Yb3+) from aqueous media with [PTA-CO2-][H+] via hydrothermal treatment were investigated and optimized. It was found that the precipitation of lanthanides form aqueous media is most efficient when the initial reaction pH lies close to 4 and the phosphine to lanthanide ratio exceeds 3:1. Finally, dilution of these precipitates in acidic media with chloride salts followed by basification with sodium hydroxide to pH > 10 yields the lanthanide hydroxides, which can be calcined to yield lanthanide oxides in a more carbon-neutral manner than the lanthanide oxalates which are currently being utilized in the industry to precipitate lanthanides from aqueous media

Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to 300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m 2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to &lt;90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], &gt;300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of &lt;15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P&lt;0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P&lt;0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Unusual Water-Soluble Imino Phosphine Ligand: Enamine and Imine Derivatives of 1,3,5-Triaza-7-phosphaadamantane (PTA)

A series of water-soluble and air-stable <i>E</i>-enamine derivatives of 1,3,5-triaza-7-phosphaadamantane (PTA), PTAC­(R)­NH₂, <b>1</b>–<b>4</b>, are reported along with data on <i>E–Z</i> isomerization and tautomerization to the imine form (PTA-CRNH). Reaction of 1,3,5-triaza-7-phosphaamantane-6-yl lithium, PTA-Li, with aromatic nitriles afforded <i>E</i>-enamine derivatives of PTA in good yield (49–91%). Phosphines <b>1</b>–<b>4</b> are stable toward water and air, and do not appear to isomerize or tautomerize, unless coordinated to a metal or oxidized. The corresponding oxides, OPTAC­(R)­NH₂ (<b>5</b>–<b>8</b>), were observed as ∼55/45 mixtures of <i>E</i> and <i>Z</i> isomers. Kinetic data on the <i>E–Z</i> isomerization is reported. Upon coordination of <b>1</b>–<b>4</b> to W­(CO)₄­(pip)₂, a κ¹-<i>P</i> enamine is formed, [W­(CO)₄(pip)­(κ¹-<i>P</i>-PTACRNH₂)]. Enamine–imine tautomerization of the metal bound phosphine was observed resulting in κ²-<i>P</i>,<i>N</i> imine complexes, [W­(CO)₄(κ²-<i>P</i>,<i>N</i>-PTA-CRNH)], <b>9</b>–<b>12</b>. The crystal structures of the κ¹-<i>P</i> enamine <b>11a</b>, κ²-<i>P</i>,<i>N</i> imine <b>9</b> and <b>12</b>, phosphines <b>1</b> and <b>3</b>, as well as phosphine oxide <b>8a</b> were obtained. DFT calculations on the various isomers of the phosphines and phosphine oxides are also reported

A Common Language for Gulf War Illness (GWI) Research Studies: GWI Common Data Elements

AIMS: The Gulf War Illness programs (GWI) of the United States Department of Veteran Affairs and the Department of Defense Congressionally Directed Medical Research Program collaborated with experts to develop Common Data Elements (CDEs) to standardize and systematically collect, analyze, and share data across the (GWI) research community. MAIN METHODS: A collective working group of GWI advocates, Veterans, clinicians, and researchers convened to provide consensus on instruments, case report forms, and guidelines for GWI research. A similar initiative, supported by the National Institute of Neurologic Disorders and Stroke (NINDS) was completed for a comparative illness, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), and provided the foundation for this undertaking. The GWI working group divided into two sub-groups (symptoms and systems assessment). Both groups reviewed the applicability of instruments and forms recommended by the NINDS ME/CFS CDE to GWI research within specific domains and selected assessments of deployment exposures. The GWI CDE recommendations were finalized in March 2018 after soliciting public comments. KEY FINDINGS: GWI CDE recommendations are organized in 12 domains that include instruments, case report forms, and guidelines. Recommendations were categorized as core (essential), supplemental-highly recommended (essential for specified conditions, study types, or designs), supplemental (commonly collected, but not required), and exploratory (reasonable to use, but require further validation). Recommendations will continually be updated as GWI research progresses. SIGNIFICANCE: The GWI CDEs reflect the consensus recommendations of GWI research community stakeholders and will allow studies to standardize data collection, enhance data quality, and facilitate data sharing