Publications by authors named "Mark Warren"

127 Publications

Multi-stimulus linear negative expansion of a breathing M(OCR)-node MOF.

Faraday Discuss 2021 Feb 12;225:133-151. Epub 2020 Nov 12.

Department of Chemistry, University of Sheffield, Brook Hill, Sheffield S3 7HF, UK.

The metal-organic framework (MeNH)[Cd(NOBDC)] (SHF-81) comprises flattened tetrahedral Cd(OCR) nodes, in which Cd(ii) centres are linked via NOBDC ligands (2-nitrobenzene-1,4-dicarboxylate) to give a doubly interpenetrated anionic network, with charge balanced by two MeNH cations per Cd centre resident in the pores. The study establishes that this is a twinned α-quartz-type structure (trigonal, space group P321, x = 1 or 2), although very close to the higher symmetry β-quartz arrangement (hexagonal, P622, x = 2 or 4) in its as-synthesised solvated form [Cd(NOBDC)]·2DMF·0.5HO (SHF-81-DMF). The activated MOF exhibits very little N uptake at 77 K, but shows significant CO uptake at 273-298 K with an isosteric enthalpy of adsorption (ΔH) at zero coverage of -27.4 kJ mol determined for the MOF directly activated from SHF-81-DMF. A series of in situ diffraction experiments, both single-crystal X-ray diffraction (SCXRD) and powder X-ray diffraction (PXRD), reveal that the MOF is flexible and exhibits breathing behaviour with observed changes as large as 12% in the a- and b-axes (|Δa|, |Δb| < 1.8 Å) and 5.5% in the c-axis (|Δc| < 0.7 Å). Both the solvated SHF-81-DMF and activated/desolvated SHF-81 forms of the MOF exhibit linear negative thermal expansion (NTE), in which pores that run parallel to the c-axis expand in diameter (a- and b-axis) while contracting in length (c-axis) upon increasing temperature. Adsorption of CO gas at 298 K also results in linear negative expansion (Δa, Δb > 0; Δc < 0; ΔV > 0). The largest change in dimensions is observed during activation/desolvation from SHF-81-DMF to SHF-81 (Δa, Δb < 0; Δc > 0; ΔV < 0). Collectively the nine in situ diffraction experiments conducted suggest the breathing behaviour is continuous, although individual desolvation and adsorption experiments do not rule out the possibility of a gating or step at intermediate geometries that is coupled with continuous dynamic behaviour towards the extremities of the breathing amplitude.
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http://dx.doi.org/10.1039/d0fd00089bDOI Listing
February 2021

Crystallizing Atomic Xenon in a Flexible MOF to Probe and Understand Its Temperature-Dependent Breathing Behavior and Unusual Gas Adsorption Phenomenon.

J Am Chem Soc 2020 Nov 10;142(47):20088-20097. Epub 2020 Nov 10.

Hoffmann Institute of Advanced Materials, Shenzhen Polytechnic, 7098 Liuxian Boulevard., Shenzhen, Guangdong 518055, China.

Flexible metal-organic frameworks (MOFs) hold great promise as smart materials for specific applications such as gas separation. These materials undergo interesting structural changes in response to guest molecules, which is often associated with unique adsorption behavior not possible for rigid MOFs. Understanding the dynamic behavior of flexible MOFs is crucial yet challenging as it involves weak host-guest interactions and subtle structural transformation not only at the atomic/molecular level but also in a nonsteady state. We report here an in-depth study on the adsorbate- and temperature-dependent adsorption in a flexible MOF by crystallizing atomic gases into its pores. Mn(ina) shows an interesting temperature-dependent response toward noble gases. Its nonmonotonic, temperature-dependent adsorption profile results in an uptake maximum at a temperature threshold, a phenomenon that is unusual. Full characterization of Xe-loaded MOF structures is performed by single-crystal and synchrotron X-ray diffraction, IR spectroscopy, and molecular modeling. The X-ray diffraction analysis offers a detailed explanation into the dynamic structural transformation and provides a convincing rationalization of the unique adsorption behavior at the molecular scale. The guest and temperature dependence of the structural breathing gives rise to an intriguing reverse of Xe/Kr adsorption selectivity as a function of temperature. The presented work may provide further understanding of the adsorption behavior of noble gases in flexible MOF structures.
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http://dx.doi.org/10.1021/jacs.0c09475DOI Listing
November 2020

Oral semaglutide in patients with type 2 diabetes and cardiovascular disease, renal impairment, or other comorbidities, and in older patients.

Postgrad Med 2020 Nov 8;132(sup2):37-47. Epub 2020 Sep 8.

Physicians East , Greenville, NC, USA.

Patients with type 2 diabetes (T2D) often have comorbidities, such as cardiovascular disease or chronic kidney disease, and a large and growing proportion of the T2D patient population is over 65 years. There are many therapies for the treatment of T2D but not all are suitable for patients with comorbidities. Oral semaglutide is a tablet formulation of a glucagon-like peptide-1 receptor agonist (GLP-1RA) and was recently approved for the treatment of T2D, representing an oral alternative to injectable GLP-1RAs. This article reviews data from: PIONEER 6, a phase 3a cardiovascular outcomes trial in patients at high cardiovascular risk; PIONEER 5, a phase 3a trial in patients with moderate renal impairment; a post-hoc analysis of PIONEER data by age; and pharmacokinetic trials investigating the effects of renal impairment, gastrointestinal disease, and hepatic impairment on the exposure of oral semaglutide. PIONEER 6 demonstrated the cardiovascular safety of oral semaglutide compared with placebo (hazard ratio: 0.79; 95% confidence interval [CI]: 0.57, 1.11; p < 0.001 for noninferiority), ruling out excess cardiovascular risk. In PIONEER 5, oral semaglutide was superior to placebo in decreasing glycated hemoglobin over 26 weeks (estimated treatment difference [ETD]: -0.8%; 95% CI: -1.0, -0.6; p < 0.0001) and body weight (ETD: -2.5 kg; 95% CI: -3.2, -1.8; p < 0.0001), and renal function was unchanged in both treatment groups. There was no effect of age on glycemic efficacy of oral semaglutide and the presence of upper gastrointestinal disease or hepatic impairment did not affect the pharmacokinetics of semaglutide. Across the trials, the safety profile of oral semaglutide was as expected for a GLP-1RA, with gastrointestinal adverse events most commonly reported. As such, oral semaglutide provides an effective oral GLP-1RA treatment option in older patients and/or those with comorbidities, with no requirements for dose adjustment.
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http://dx.doi.org/10.1080/00325481.2020.1800286DOI Listing
November 2020

Probing the structural and electronic response of Magnus green salt compounds [Pt(NHR)][PtCl] (R = H, CH) to pressure.

Phys Chem Chem Phys 2020 Aug 29;22(31):17668-17676. Epub 2020 Jul 29.

EaStCHEM School of Chemistry, University of Edinburgh, Edinburgh, UK.

Despite possessing the desirable crystal packing and short PtPt stacking distances required for a large piezoresistive response, the conductivity-pressure response of the Magnus green salt [Pt(NH)][PtCl] is extremely sluggish. Through a combination of high-pressure X-ray diffraction and hybrid-DFT solid state calculations this study demonstrates that the poor conductivity-pressure response is due to a low volumetric compression anisotropy, a relatively large ambient pressure band gap and a lack of dispersion in the conduction band. Ligand modification (from NH to NHCH) does not enhance the piezoresistive response, causing even lower anisotropy of the volumetric compression and an unexpected phase transition at above 2 GPa. This study demonstrates that consideration of frontier band dispersion is a key design criterion, alongside crystal packing and PtPt stacking distances, for piezoresistive materials.
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http://dx.doi.org/10.1039/d0cp03280hDOI Listing
August 2020

Direct Crystallographic Observation of CO Captured in Zig Zag Channels of a Copper(I) Metal-Organic Framework.

Inorg Chem 2020 May 16;59(9):6376-6381. Epub 2020 Apr 16.

Department of Chemistry and MacDiarmid Institute for Advanced Materials and Nanotechnology, University of Otago, PO Box 56, Dunedin 9054, New Zealand.

Single crystal X-ray diffraction has been used to study the CO absorption sites in a microporous Cu-MOF, [Cu(py-pzpypz)(μ-CN)] () (where py-pzpypz = 4-(4-pyridyl)-2,5-dipyrazyl-pyridine), which features zigzag-shaped channels, at a range of CO pressures (1, 5, and 10 bar) and at two temperatures (240 and 298 K). Unlike the acetonitrile molecules in the as-synthesized MOF, , the CO molecules in ( = 0.8, 0.7, 0.45) are preferentially centered on the vertices of each zig and zag, which allows for weak (azine) C-H···OCO interactions with the H atoms on the electron-deficient pyrazine and pyridine rings of the MOF.
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http://dx.doi.org/10.1021/acs.inorgchem.0c00471DOI Listing
May 2020

Semaglutide improves health-related quality of life versus placebo when added to standard of care in patients with type 2 diabetes at high cardiovascular risk (SUSTAIN 6).

Diabetes Obes Metab 2020 08 27;22(8):1339-1347. Epub 2020 Apr 27.

Diabetes Research Unit Cymru, Swansea University Medical School, Swansea, UK.

Aim: To assess what drives change in health-related quality of life (HRQoL) in type 2 diabetes in the SUSTAIN 6 trial and identify potential mediators of the treatment effect of semaglutide on HRQoL scores.

Materials And Methods: The Short Form (SF)-36v2® questionnaire [comprising physical component summary (PCS) and mental component summary (MCS)] was used to assess changes in HRQoL from baseline to week 104, by treatment, in a prespecified analysis. This post-hoc analysis assessed change in PCS and MCS using the following factors as parameter/covariate, using descriptive statistics and linear regressions: major adverse cardiac events, hypoglycaemia, gastrointestinal adverse events, at least one episode of nausea, vomiting or diarrhoea, and change in glycated haemoglobin (HbA1c), body weight, blood pressure, heart rate and estimated glomerular filtration rate.

Results: Mean change in overall PCS score was +1.0 with semaglutide versus +0.4 with placebo, and +0.5 versus -0.2 for MCS. The treatment effect of semaglutide versus placebo (unadjusted estimate) was 0.7 [(95% confidence interval 0.1, 1.2); P = 0.018] on PCS and this was reduced when adjusted for change in HbA1c [0.4 (-0.2, 1.0), P = .167] and body weight [0.3 (-0.3, 0.9), P = .314]. The unadjusted treatment effect on MCS [0.7 (-0.0, 1.5), P = .054] was only reduced when adjusted for change in HbA1c [0.3 (-0.4, 1.1), P = .397]. When adjusting for all other parameters separately, the estimated effect of semaglutide on PCS and MCS qualitatively did not change.

Conclusions: Semaglutide improved HRQoL versus placebo; greater improvements with semaglutide versus placebo were possibly mediated, in part, by change in HbA1c and body weight. Clinicaltrials.gov: NCT01720446 (SUSTAIN 6).
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http://dx.doi.org/10.1111/dom.14039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383680PMC
August 2020

Pressure-induced non-innocence in bis(1,2-dionedioximato)Pt(ii) complexes: an experimental and theoretical study of their insulator-metal transitions.

Phys Chem Chem Phys 2020 Mar 11;22(12):6677-6689. Epub 2020 Mar 11.

EaStCHEM School of Chemistry, University of Edinburgh, Edinburgh, UK.

Bis(1,2-dionedioximato) complexes of Pt(ii) are known for their propensity to form linear chains of metal complexes in the solid state, and under the application of pressure members of the family display interesting optical and conductive properties. Two examples, Pt(bqd) and Pt(dmg), are known to undergo insulator-to-metal-to-insulator transitions, with the metallic state reached at 0.8-1.4 GPa and 5 GPa, respectively. Previous interpretations of these materials' behaviour focused on the role of the filled d and vacant p orbitals on platinum, with little consideration to the role of the ligand. Here, the pressure-structural behaviour of Pt(bqd) is investigated through single crystal X-ray diffraction, the first such study on this material. The difference in conductive behaviour under pressure between Pt(bqd) and Pt(dmg) is then interpreted through a combination of experimental and computational methods, including conductivity measurements under high pressure and electronic structure calculations. Our computational work reveals the significant contribution from ligand low-lying vacant π-orbitals to the frontier orbitals and bands in these complexes, and provides an explanation for the experimentally observed re-entrant insulator-to-metal-to-insulator transitions, and the differences in behaviour between the two compounds.
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http://dx.doi.org/10.1039/c9cp06749cDOI Listing
March 2020

"Heart Oddity": Intrinsically Reduced Excitability in the Right Ventricle Requires Compensation by Regionally Specific Stress Kinase Function.

Front Physiol 2020 18;11:86. Epub 2020 Feb 18.

Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT, United States.

The traditional view of ventricular excitation and conduction is an all-or-nothing response mediated by a regenerative activation of the inward sodium channel, which gives rise to an essentially conduction velocity (CV). However, whereas there is no obvious biological need to tune-up ventricular conduction, the principal molecular components determining CV, such as sodium channels, inward-rectifier potassium channels, and gap junctional channels, are known targets of the "stress" protein kinases PKA and calcium/calmodulin dependent protein kinase II (CaMKII), and are thus by signal pathways converging on these kinases. In this mini-review we will expose deficiencies and controversies in our current understanding of how ventricular conduction is regulated by stress kinases, with a special focus on the chamber-specific dimension in this regulation. In particular, we will highlight an odd property of cardiac physiology: uniform CV in ventricles requires co-existence of mutually opposing gradients in cardiac excitability and stress kinase function. While the biological advantage of this peculiar feature remains obscure, it is important to recognize the clinical implications of this phenomenon pertinent to inherited or acquired conduction diseases and therapeutic interventions modulating activity of PKA or CaMKII.
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http://dx.doi.org/10.3389/fphys.2020.00086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7040197PMC
February 2020

Boots.

Authors:
Mark B Warren

Schizophr Bull 2020 Feb 20. Epub 2020 Feb 20.

Department of Psychiatry and Behavioral Sciences, University of Washington, and Boise Veterans Administration Medical Center, Boise, Idaho.

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http://dx.doi.org/10.1093/schbul/sbaa015DOI Listing
February 2020

Boots.

Authors:
Mark B Warren

Schizophr Bull 2020 Feb 20. Epub 2020 Feb 20.

Department of Psychiatry and Behavioral Sciences, University of Washington, and Boise Veterans Administration Medical Center, Boise, Idaho.

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http://dx.doi.org/10.1093/schbul/sbaa015DOI Listing
February 2020

Interactions of Oral Molecular Excipients with Breast Cancer Resistance Protein, BCRP.

Mol Pharm 2020 03 10;17(3):748-756. Epub 2020 Feb 10.

Department of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and Medicine, University of California, San Francisco, California 94158, United States.

Mechanistic-understanding-based selection of excipients may improve formulation development strategies for generic drug products and potentially accelerate their approval. Our study aimed at investigating the effects of molecular excipients present in orally administered FDA-approved drug products on the intestinal efflux transporter, BCRP (), which plays a critical role in drug absorption with potential implications on drug safety and efficacy. We determined the interactions of 136 oral molecular excipients with BCRP in isolated membrane vesicles and identified 26 excipients as BCRP inhibitors with IC values less than 5 μM using H-cholecystokinin octapeptide (H-CCK8). These BCRP inhibitors belonged to three functional categories of excipients: dyes, surfactants, and flavoring agents. Compared with noninhibitors, BCRP inhibitors had significantly higher molecular weights and SLogP values. The inhibitory effects of excipients identified in membrane vesicles were also evaluated in BCRP-overexpressing HEK293 cells at similar concentrations. Only 1 of the 26 inhibitors of BCRP identified in vesicles inhibited BCRP-mediated H-oxypurinol uptake by more than 50%, consistent with the notion that BCRP inhibition depends on transmembrane or intracellular availability of the inhibitors. Collectively, the results of this study provide new information on excipient selection during the development of drug products with active pharmaceutical ingredients that are BCRP substrates.
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http://dx.doi.org/10.1021/acs.molpharmaceut.9b00658DOI Listing
March 2020

Clinical Use of IDegLira: Initiation to Titration After Basal Insulin.

Clin Diabetes 2020 Jan;38(1):62-70

Main Line Health, Wynnewood, PA.

Delayed treatment intensification is common in U.S. patients with type 2 diabetes uncontrolled on basal insulin. Concerns about weight gain, hypoglycemia, increased regimen complexity, and additional copayments may lead to reluctance to initiate prandial insulin. IDegLira is a titratable, fixed-ratio coformulation that combines the advantages of insulin degludec and the glucagon-like peptide 1 receptor agonist liraglutide in a single once-daily injection and mitigates the side effects associated with each component. Clinical trials have demonstrated that IDegLira improves glycemic control without the increased risk of hypoglycemia and weight gain observed with basal insulin up-titration and the addition of prandial insulin, and this is achieved using twice-weekly titration. Clinical trials and real-world studies have also shown that IDegLira has the potential to reduce therapeutic and titration inertia. However, better outcomes could be achieved with IDegLira initiation in suitable patients with timely titration and by providers sharing their experience with this combination product. This review describes considerations for initiation, titration, and intensification of IDegLira in patients previously receiving basal insulin.
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http://dx.doi.org/10.2337/cd19-0015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6969665PMC
January 2020

Winter weather controls net influx of atmospheric CO on the north-west European shelf.

Sci Rep 2019 12 27;9(1):20153. Epub 2019 Dec 27.

Plymouth Marine Laboratory, Plymouth, UK.

Shelf seas play an important role in the global carbon cycle, absorbing atmospheric carbon dioxide (CO) and exporting carbon (C) to the open ocean and sediments. The magnitude of these processes is poorly constrained, because observations are typically interpolated over multiple years. Here, we used 298500 observations of CO fugacity (fCO) from a single year (2015), to estimate the net influx of atmospheric CO as 26.2 ± 4.7 Tg C yr over the open NW European shelf. CO influx from the atmosphere was dominated by influx during winter as a consequence of high winds, despite a smaller, thermally-driven, air-sea fCO gradient compared to the larger, biologically-driven summer gradient. In order to understand this climate regulation service, we constructed a carbon-budget supplemented by data from the literature, where the NW European shelf is treated as a box with carbon entering and leaving the box. This budget showed that net C-burial was a small sink of 1.3 ± 3.1 Tg C yr, while CO efflux from estuaries to the atmosphere, removed the majority of river C-inputs. In contrast, the input from the Baltic Sea likely contributes to net export via the continental shelf pump and advection (34.4 ± 6.0 Tg C yr).
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http://dx.doi.org/10.1038/s41598-019-56363-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934492PMC
December 2019

Shape-memory effects in molecular crystals.

Nat Commun 2019 Aug 19;10(1):3723. Epub 2019 Aug 19.

New York University Abu Dhabi, PO Box 129188, Abu Dhabi, UAE.

Molecular crystals can be bent elastically by expansion or plastically by delamination into slabs that glide along slip planes. Here we report that upon bending, terephthalic acid crystals can undergo a mechanically induced phase transition without delamination and their overall crystal integrity is retained. Such plastically bent crystals act as bimorphs and their phase uniformity can be recovered thermally by taking the crystal over the phase transition temperature. This recovers the original straight shape and the crystal can be bent by a reverse thermal treatment, resulting in shape memory effects akin of those observed with some metal alloys and polymers. We anticipate that similar memory and restorative effects are common for other molecular crystals having metastable polymorphs. The results demonstrate the advantage of using intermolecular interactions to accomplish mechanically adaptive properties with organic solids that bridge the gap between mesophasic and inorganic materials in the materials property space.
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http://dx.doi.org/10.1038/s41467-019-11612-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700106PMC
August 2019

Safety and Efficacy of 5 Years of Treatment With Recombinant Human Parathyroid Hormone in Adults With Hypoparathyroidism.

J Clin Endocrinol Metab 2019 11;104(11):5136-5147

Section of Endocrinology, University of Chicago Medicine, Chicago, Illinois.

Context: Conventional hypoparathyroidism treatment with oral calcium and active vitamin D is aimed at correcting hypocalcemia but does not address other physiologic defects caused by PTH deficiency.

Objective: To evaluate long-term safety and tolerability of recombinant human PTH (1-84) [rhPTH(1-84)].

Design: Open-label extension study; 5-year interim analysis.

Setting: 12 US centers.

Patients: Adults (N = 49) with chronic hypoparathyroidism.

Intervention(s): rhPTH(1-84) 25 or 50 µg/d initially, with 25-µg adjustments permitted to a 100 µg/d maximum.

Main Outcome Measure(s): Safety parameters; composite efficacy outcome was the proportion of patients with ≥50% reduction in oral calcium (or ≤500 mg/d) and calcitriol (or ≤0.25 µg/d) doses, and albumin-corrected serum calcium normalized or maintained compared with baseline, not exceeding upper limit of normal.

Results: Forty patients completed 60 months of treatment. Mean albumin-corrected serum calcium levels remained between 8.2 and 8.7 mg/dL. Between baseline and month 60, levels ± SD of urinary calcium, serum phosphorus, and calcium-phosphorus product decreased by 101.2 ± 236.24 mg/24 hours, 1.0 ± 0.78 mg/dL, and 8.5 ± 8.29 mg2/dL2, respectively. Serum creatinine level and estimated glomerular filtration rate were unchanged. Treatment-emergent adverse events (AEs) were reported in 48 patients (98.0%; hypocalcemia, 36.7%; muscle spasms, 32.7%; paresthesia, 30.6%; sinusitis, 30.6%; nausea, 30.6%) and serious AEs in 13 (26.5%). At month 60, 28 patients (70.0%) achieved the composite efficacy outcome. Bone turnover markers increased, peaked at ∼12 months, and then declined to values that remained above baseline.

Conclusion: Treatment with rhPTH(1-84) for 5 years demonstrated a safety profile consistent with previous studies and improved key biochemical parameters.
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http://dx.doi.org/10.1210/jc.2019-01010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760337PMC
November 2019

12th GCC Closed Forum: critical reagents; oligonucleotides; CoA; method transfer; HRMS; flow cytometry; regulatory findings; stability and immunogenicity.

Bioanalysis 2019 Jun 19;11(12):1129-1138. Epub 2019 Jul 19.

WuXi Apptec, Plainsboro, NJ 08536, USA.

The 12th GCC Closed Forum was held in Philadelphia, PA, USA, on 9 April 2018. Representatives from international bioanalytical Contract Research Organizations were in attendance in order to discuss scientific and regulatory issues specific to bioanalysis. The issues discussed at the meeting included: critical reagents; oligonucleotides; certificates of analysis; method transfer; high resolution mass spectrometry; flow cytometry; recent regulatory findings and case studies involving stability and nonclinical immunogenicity. Conclusions and consensus from discussions of these topics are included in this article.
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http://dx.doi.org/10.4155/bio-2019-0131DOI Listing
June 2019

Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes.

N Engl J Med 2019 08 11;381(9):841-851. Epub 2019 Jun 11.

From the Peter Munk Cardiac Centre, University Health Network, Department of Medicine and the Heart and Stroke Richard Lewar Centre, University of Toronto, Toronto General Hospital Research Institute, and the Ted Rogers Centre for Heart Research, Toronto (M.H.), and the C-endo Diabetes and Endocrinology Clinic, Calgary, AB (S.D.P.) - all in Canada; Medical Clinic III, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, and the Paul Langerhans Institute Dresden of Helmholtz Zentrum München at Technische Universität Dresden, German Center for Diabetes Research, Dresden, Germany (A.L.B.); the Division of Diabetes and Nutritional Sciences, Rayne Institute, King's College London, London (A.L.B.), and the Diabetes Research Unit Cymru, Swansea University Medical School, Swansea (S.C.B.) - both in the United Kingdom; Novo Nordisk, Søborg, Denmark (M.D., O.K.J., M.T.); the Division of Endocrinology, Diabetes, and Metabolism, Ohio State University, Columbus (K.D.); Centro de Pesquisas Clínicas/Diagnosticos da America Clinical Research Center, São Paulo (F.G.E., D.R.F.); the Departments of Internal Medicine and Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas (I.L.); the Diabetes Unit, Division of Internal Medicine, Hadassah Hebrew University Hospital, Jerusalem (O.M.); the Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands (C.J.T); Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, University of Copenhagen, Gentofte, Denmark (T.V.); and Physicians East, Greenville, NC (M.L.W.).

Background: Establishing cardiovascular safety of new therapies for type 2 diabetes is important. Safety data are available for the subcutaneous form of the glucagon-like peptide-1 receptor agonist semaglutide but are needed for oral semaglutide.

Methods: We assessed cardiovascular outcomes of once-daily oral semaglutide in an event-driven, randomized, double-blind, placebo-controlled trial involving patients at high cardiovascular risk (age of ≥50 years with established cardiovascular or chronic kidney disease, or age of ≥60 years with cardiovascular risk factors only). The primary outcome in a time-to-event analysis was the first occurrence of a major adverse cardiovascular event (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke). The trial was designed to rule out 80% excess cardiovascular risk as compared with placebo (noninferiority margin of 1.8 for the upper boundary of the 95% confidence interval for the hazard ratio for the primary outcome).

Results: A total of 3183 patients were randomly assigned to receive oral semaglutide or placebo. The mean age of the patients was 66 years; 2695 patients (84.7%) were 50 years of age or older and had cardiovascular or chronic kidney disease. The median time in the trial was 15.9 months. Major adverse cardiovascular events occurred in 61 of 1591 patients (3.8%) in the oral semaglutide group and 76 of 1592 (4.8%) in the placebo group (hazard ratio, 0.79; 95% confidence interval [CI], 0.57 to 1.11; P<0.001 for noninferiority). Results for components of the primary outcome were as follows: death from cardiovascular causes, 15 of 1591 patients (0.9%) in the oral semaglutide group and 30 of 1592 (1.9%) in the placebo group (hazard ratio, 0.49; 95% CI, 0.27 to 0.92); nonfatal myocardial infarction, 37 of 1591 patients (2.3%) and 31 of 1592 (1.9%), respectively (hazard ratio, 1.18; 95% CI, 0.73 to 1.90); and nonfatal stroke, 12 of 1591 patients (0.8%) and 16 of 1592 (1.0%), respectively (hazard ratio, 0.74; 95% CI, 0.35 to 1.57). Death from any cause occurred in 23 of 1591 patients (1.4%) in the oral semaglutide group and 45 of 1592 (2.8%) in the placebo group (hazard ratio, 0.51; 95% CI, 0.31 to 0.84). Gastrointestinal adverse events leading to discontinuation of oral semaglutide or placebo were more common with oral semaglutide.

Conclusions: In this trial involving patients with type 2 diabetes, the cardiovascular risk profile of oral semaglutide was not inferior to that of placebo. (Funded by Novo Nordisk; PIONEER 6 ClinicalTrials.gov number, NCT02692716.).
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http://dx.doi.org/10.1056/NEJMoa1901118DOI Listing
August 2019

High Pressure Crystal Structure and Electrical Properties of a Single Component Molecular Crystal [Ni(dddt)] (dddt = 5,6-dihydro-1,4-dithiin-2,3-dithiolate).

Molecules 2019 May 14;24(10). Epub 2019 May 14.

Condensed Molecular Materials Laboratory RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan.

Single-component molecular conductors form an important class of materials showing exotic quantum phenomena, owing to the range of behavior they exhibit under physical stimuli. We report the effect of high pressure on the electrical properties and crystal structure of the single-component crystal [Ni(dddt)] (where dddt = 5,6-dihydro-1,4-dithiin-2,3-dithiolate). The system is isoelectronic and isostructural with [Pd(dddt)], which is the first example of a single-component molecular crystal that exhibits nodal line semimetallic behavior under high pressure. Systematic high pressure four-probe electrical resistivity measurements were performed up to 21.6 GPa, using a Diamond Anvil Cell (DAC), and high pressure single crystal synchrotron X-ray diffraction was performed up to 11.2 GPa. We found that [Ni(dddt)] initially exhibits a decrease of resistivity upon increasing pressure but, unlike [Pd(dddt)], it shows pressure-independent semiconductivity above 9.5 GPa. This correlates with decreasing changes in the unit cell parameters and intermolecular interactions, most notably the - stacking distance within chains of [Ni(dddt)] molecules. Using first-principles density functional theory (DFT) calculations, based on the experimentally-determined crystal structures, we confirm that the band gap decreases with increasing pressure. Thus, we have been able to rationalize the electrical behavior of [Ni(dddt)] in the pressure-dependent regime, and suggest possible explanations for its pressure-independent behavior at higher pressures.
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http://dx.doi.org/10.3390/molecules24101843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6572596PMC
May 2019

Highly stable fullerene-based porous molecular crystals with open metal sites.

Nat Mater 2019 07 13;18(7):740-745. Epub 2019 May 13.

EaStCHEM, School of Chemistry, University of Edinburgh, Edinburgh, UK.

The synthesis of conventional porous crystals involves building a framework using reversible chemical bond formation, which can result in hydrolytic instability. In contrast, porous molecular crystals assemble using only weak intermolecular interactions, which generally do not provide the same environmental stability. Here, we report that the simple co-crystallization of a phthalocyanine derivative and a fullerene (C or C) forms porous molecular crystals with environmental stability towards high temperature and hot aqueous base or acid. Moreover, by using diamond anvil cells and synchrotron single-crystal measurements, stability towards extreme pressure (>4 GPa) is demonstrated, with the stabilizing fullerene held between two phthalocyanines and the hold tightening at high pressure. Access to open metal centres within the porous molecular co-crystal is demonstrated by in situ crystallographic analysis of the chemisorption of pyridine, oxygen and carbon monoxide. This suggests strategies for the formation of highly stable and potentially functional porous materials using only weak van der Waals intermolecular interactions.
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http://dx.doi.org/10.1038/s41563-019-0361-0DOI Listing
July 2019

Recommendations for classification of commercial LBA kits for biomarkers in drug development from the GCC for bioanalysis.

Bioanalysis 2019 Apr 17;11(7):645-653. Epub 2019 Apr 17.

WuXi Apptec, Plainsboro, NJ, USA.

Over the last decade, the use of biomarker data has become integral to drug development. Biomarkers are not only utilized for internal decision-making by sponsors; they are increasingly utilized to make critical decisions for drug safety and efficacy. As the regulatory agencies are routinely making decisions based on biomarker data, there has been significant scrutiny on the validation of biomarker methods. Contract research organizations regularly use commercially available immunoassay kits to validate biomarker methods. However, adaptation of such kits in a regulated environment presents significant challenges and was one of the key topics discussed during the 12th Global Contract Research Organization Council for Bioanalysis (GCC) meeting. This White Paper reports the GCC members' opinion on the challenges facing the industry and the GCC recommendations on the classification of commercial kits that can be a win-win for commercial kit vendors and end users.
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http://dx.doi.org/10.4155/bio-2019-0072DOI Listing
April 2019

Patient-reported outcomes from a randomized, crossover trial comparing a pen injector with insulin degludec versus a pen injector with insulin glargine U100 in patients with type 2 diabetes.

Curr Med Res Opin 2019 09 21;35(9):1623-1629. Epub 2019 May 21.

Meridien Research, Bradenton, FL, USA.

Type 2 diabetes (T2D) is associated with insulin resistance and deteriorated glycemic control that can be restored with insulin injections. Choice of insulin pen injector may affect complexity, adherence, efficacy of treatment and health-related quality of life. We describe detailed patient-reported outcomes (PROs) on treatment impact and preference comparing insulin degludec (degludec) using FlexTouch versus insulin glargine U100 (glargine U100) with SoloStar pen injector. In this randomized, multicenter (USA), open-label, crossover, treat-to-target study (NCT01570751), patients with T2D using high-dose insulin (≥81 U/day from vials) were randomized ( = 145) 1:1 to 16 weeks of degludec U200 (3 mL FlexTouch) followed by 16 weeks of glargine U100 (3 mL SoloStar) or vice versa. PRO questionnaires assessed treatment impact and patient preference of pen injectors. Significantly more patients ( < .01) considered FlexTouch "extremely easy" for learning (62.5 vs. 43.0%), maintaining (63.2 vs. 42.2%) and adjusting the dose (63.2 vs. 44.4%), and significantly more were "very" or "extremely confident" in using the device (60.3 vs. 36.3%) and in its accuracy (50.7 vs. 30.4%) versus SoloStar. Significantly more were "not at all bothered" by device discomfort (74.3 vs. 54.1%), whereas device size (83.8 vs. 80.0%) or public use (69.9 vs. 60.7%) were numerically in favor of FlexTouch. Significantly more patients preferred degludec treatment with FlexTouch (59 vs. 22%), preferred to continue (67 vs. 15%) and recommend (67 vs. 14%) use of FlexTouch compared with SoloStar with glargine U100. In this randomized, crossover trial, lower treatment impact and higher patient preference were reported for FlexTouch versus SoloStar pen injectors.
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http://dx.doi.org/10.1080/03007995.2019.1605769DOI Listing
September 2019

Photocrystallographic Studies on Transition Metal Nitrito Metastable Linkage Isomers: Manipulating the Metastable State.

Acc Chem Res 2019 Apr 27;52(4):1079-1088. Epub 2019 Mar 27.

Department of Chemistry , University of Bath , Bath BA2 7AY , U.K.

The design of solid-state materials whose properties and functions can be manipulated in a controlled manner by the application of light is an important objective in modern materials chemistry. When the material changes property or function, it is helpful if a simple measurable response, such as a change in color, can be detected. Potential applications for such materials are wide ranging, from data storage to smart windows. With the growing emphasis on solid-state materials that have two or more accessible energy states and which exhibit bistability, attention has turned to transition metal complexes that contain ambidentate ligands that can switch between linkage isomeric forms when activated by light. Suitable ligands that show promise in this area include nitrosyls, nitro groups, and coordinated sulfur dioxide molecules, each of which can coordinate to a metal center in more than one bonding mode. A nitrosyl normally coordinates through its N atom (η-NO) but when photoactivated can undergo isomerism and coordinate through its O atom (η-ON). At a molecular level, converting between these two configurations can act as an "on/off" switch. The analysis of such materials has been aided by the development of photocrystallographic techniques, which allow the full three-dimensional structure of a single crystal of a complex, under photoactivation, to be determined, when it is in either a metastable or short-lived excited state. The technique effectively brings the dimension of "time" to the crystallographic experiment and brings us closer to being able to watch solid-state processes occur in real time. In this Account, we highlight the advances made in photocrystallography for studying solid-state, photoactivated linkage isomerism and describe the factors that favor the switching process and which allow complete switching between isomers. We demonstrate that control of temperature is key to achieving either a metastable state or an excited state with a specific lifetime. We draw our conclusions from published work on the formation of photoactivated metastable states for nitrosyl and sulfur dioxide complexes and from our own work on photoactivated switching between nitro and nitrito groups. We show that efficient switching between isomers is dependent on the wavelength of light used, on the temperature at which the experiment is carried out, on the flexibility of the crystal lattice, and on both the electronic and steric environment of the ambidentate ligand undergoing isomerism. We have designed and prepared a number of nitro/nitrito isomeric metal complexes that undergo reversible 100% conversion between the two forms at temperatures close to room temperature. Through our fine control over the generation of the metastable states, it should be possible to effectively "dial up" a suitable temperature to give a metastable or an excited state with a desired lifetime.
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http://dx.doi.org/10.1021/acs.accounts.9b00018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005940PMC
April 2019

Conduction in the right and left ventricle is differentially regulated by protein kinases and phosphatases: implications for arrhythmogenesis.

Am J Physiol Heart Circ Physiol 2019 06 15;316(6):H1507-H1527. Epub 2019 Mar 15.

Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah , Salt Lake City, Utah.

The "stress" kinases cAMP-dependent protein kinase (PKA) and calcium/calmodulin-dependent protein kinase II (CaMKII), phosphorylate the Na channel Nav1.5 subunit to regulate its function. However, how the channel regulation translates to ventricular conduction is poorly understood. We hypothesized that the stress kinases positively and differentially regulate conduction in the right (RV) and the left (LV) ventricles. We applied the CaMKII blocker KN93 (2.75 μM), PKA blocker H89 (10 μM), and broad-acting phosphatase blocker calyculin (30 nM) in rabbit hearts paced at a cycle length (CL) of 150-8,000 ms. We used optical mapping to determine the distribution of local conduction delays (inverse of conduction velocity). Control hearts exhibited constant and uniform conduction at all tested CLs. Calyculin (15-min perfusion) accelerated conduction, with greater effect in the RV (by 15.3%) than in the LV (by 4.1%; < 0.05). In contrast, both KN93 and H89 slowed down conduction in a chamber-, time-, and CL-dependent manner, with the strongest effect in the RV outflow tract (RVOT). Combined KN93 and H89 synergistically promoted conduction slowing in the RV (KN93: 24.7%; H89: 29.9%; and KN93 + H89: 114.2%; = 0.0016) but not the LV. The progressive depression of RV conduction led to conduction block and reentrant arrhythmias. Protein expression levels of both the CaMKII-δ isoform and the PKA catalytic subunit were higher in the RVOT than in the apical LV ( < 0.05). Thus normal RV conduction requires a proper balance between kinase and phosphatase activity. Dysregulation of this balance due to pharmacological interventions or disease is potentially proarrhythmic. We show that uniform ventricular conduction requires a precise physiological balance of the activities of calcium/calmodulin-dependent protein kinase II (CaMKII), PKA, and phosphatases, which involves region-specific expression of CaMKII and PKA. Inhibiting CaMKII and/or PKA activity elicits nonuniform conduction depression, with the right ventricle becoming vulnerable to the development of conduction disturbances and ventricular fibrillation/ventricular tachycardia.
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http://dx.doi.org/10.1152/ajpheart.00660.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6620685PMC
June 2019

Mechanical properties of the ferroelectric metal-free perovskite [MDABCO](NH)I.

Chem Commun (Camb) 2019 Apr 14;55(27):3911-3914. Epub 2019 Mar 14.

Department of Chemistry and Catalysis Research Center, Technical University of Munich, Lichtenbergstrasse 4, D-85748 Garching, Germany.

The metal-free hybrid organic-inorganic perovskite [MDABCO](NH)I (with MDABCO = N-methyl-1,4-diazabicyclo[2.2.2]octane) was recently discovered to exhibit an excellent ferroelectric performance, challenging established ceramic ferroelectrics. We here probe the mechanical properties of [MDABCO](NH)I by combining high pressure single crystal X-ray diffraction and nanoindentation, underlining the exceptional role and opportunities that come with the use of sustainable, metal-free perovskite ferroelectrics.
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http://dx.doi.org/10.1039/c9cc00580cDOI Listing
April 2019

Modulating proton diffusion and conductivity in metal-organic frameworks by incorporation of accessible free carboxylic acid groups.

Chem Sci 2019 Feb 2;10(5):1492-1499. Epub 2018 Nov 2.

School of Chemistry , University of Manchester , Manchester M13 9PL , UK . Email: ; Email:

Three multi-carboxylic acid functionalised ligands have been designed, synthesised and utilised to prepare the new barium-based MOFs, MFM-510, -511, and -512, which show excellent stability to water-vapour. MFM-510 and MFM-511 show moderate proton conductivities (2.1 × 10 and 5.1 × 10 S cm, respectively) at 99% RH and 298 K, attributed to the lack of free protons or hindered proton diffusion within the framework structures. In contrast, MFM-512, which incorporates a pendant carboxylic acid group directed into the pore of the framework, shows a two orders of magnitude enhancement in proton conductivity (2.9 × 10 S cm). Quasi-elastic neutron scattering (QENS) suggests that the proton dynamics of MFM-512 are mediated by "free diffusion inside a sphere" confirming that incorporation of free carboxylic acid groups within the pores of MOFs is an efficient albeit synthetically challenging strategy to improve proton conductivity.
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http://dx.doi.org/10.1039/c8sc03022gDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354967PMC
February 2019

Hydrogenase biomimics containing redox-active ligands: Fe(CO)(μ-edt)(κ-bpcd) with electron-acceptor 4,5-bis(diphenylphosphino)-4-cyclopenten-1,3-dione (bpcd) as a potential [Fe-S] surrogate.

Dalton Trans 2019 May;48(18):6051-6060

Department of Chemistry, King's College London, Britannia House, 7 Trinity Street, London SE1 1DB, UK.

[FeFe]-hydrogenases contain strongly electronically coupled diiron [2Fe]H and tetrairon [Fe4-S4]H clusters, and thus much recent effort has focused on the chemistry of diiron-dithiolate biomimics with appended redox-active ligands. Here we report on the synthesis and electrocatalytic activity of Fe2(CO)4(μ-edt)(κ2-bpcd) (2) in which the electron-acceptor 4,5-bis(diphenylphosphino)-4-cyclopenten-1,3-dione (bpcd) acts as a surrogate of the [Fe4-S4]H sub-cluster. The complex is prepared in low yield but has been fully characterised, including a crystallographic study which shows that the diphosphine adopts a basal-apical coordination geometry in the solid state. Cyclic voltammetry shows that 2 undergoes four reduction events with DFT studies confirming that the first reduction is localised on the low-lying π* system of the diphosphine ligand. The addition of the second electron furnishes a triplet dianion that exhibits spin density distributed over the diphosphine and diiron subunits. Protonation at the Fe-Fe bond of the triplet dianion furnishes the corresponding bridging hydride as the thermodynamically favoured species that contains a reduced bpcd ligand. Complex 2 functions as a catalyst for proton-reduction at its second reduction potential, in contrast to the related 2,3-bis(diphenylphosphino)maleic anhydride (bma) complex, Fe2(CO)4(μ-pdt)(κ2-bma) (1), which shows similar electrochemical behaviour but is not catalytically active. The difference in chemical behaviour is attributed to greater stability of the 4-cyclopenten-1,3-dione platform in 2 as compared to the maleic anhydride ring of the bma ligand in 1 following the uptake of the second electron. Thus protonation of the Fe-Fe bond in the 22- affords a species which is stable enough to undergo a further reduction-protonation event, unlike the bma ligand whose maleic anhydride ring undergoes deleterious C-O bond scission upon protonation or reaction with adventitious moisture. DFT studies, however, suggest that electron-transfer from the diphosphine to the diiron centre is not significant, probably due to their poor redox levelling. Thus, while the diphosphine is readily reduced, the added electron is apparently not utilised in proton-reduction and hence cannot truly be considered as an [Fe4-S4]H surrogate.
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http://dx.doi.org/10.1039/c8dt04906hDOI Listing
May 2019

Internationalising Research Methods Teaching of Undergraduate Health Professionals.

J Med Imaging Radiat Sci 2018 03 2;49(1):97-105. Epub 2018 Jan 2.

School of Health Sciences, University of Liverpool, Liverpool, UK.

Objective: The project aims were: (1) identifying the pedagogical impact of collaborative student experience on student understanding of research methods and (2) evaluating the perceived value of providing students with an international perspective on their professional practice.

Methods: Student cohorts from year 1 of the University of Liverpool (UoL) (n = 80) and year 2 of the Royal Melbourne Institute of Technology University (RMIT) (n = 128) undergraduate Medical Radiation Science degree programmes participated in the intervention as part of their teaching. Students were tasked with designing, deploying, and analysing data from survey-based research projects and invited to provide feedback via an anonymous and voluntary online survey (UoL students) or an equivalent paper-based survey (RMIT students), comprising both quantitative (Likert) and qualitative (open) questions.

Results: Responses were received from 83% of RMIT and 31% of UoL students. Over 42% of respondents enjoyed the opportunity to interact with overseas peers, while 14.7% did not; 40% of respondents felt the intervention helped in their understanding of research methods, whilst 28% indicated it had not. The main positive themes were learning the research process, team working skills, networking opportunities, and understanding cultural differences. Interpreting data were invaluable; only a minority valued the engagement with their overseas counterparts. There was poor engagement with social media.

Conclusions: Students reported clear value of the innovation for learning research skills and process. The extent of research skills learning supports changes in research activity and culture in the past 10 years. With internationalisation becoming increasingly important in today's health care economy, the degree to which the students identified this aspect of the research as a key learning point highlights the benefits of the active approach. The negative appraisal of the social media support was interpreted as a response to the platform (WhatsApp) and privacy issues with sharing phone numbers.
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http://dx.doi.org/10.1016/j.jmir.2017.11.003DOI Listing
March 2018

Modulation of σ-Alkane Interactions in [Rh(L)(alkane)] Solid-State Molecular Organometallic (SMOM) Systems by Variation of the Chelating Phosphine and Alkane: Access to η,η-σ-Alkane Rh(I), η-σ-Alkane Rh(III) Complexes, and Alkane Encapsulation.

J Am Chem Soc 2018 Nov 24;140(44):14958-14970. Epub 2018 Oct 24.

Chemistry Research Laboratories , University of Oxford , Oxford OX1 3TA , United Kingdom.

Solid/gas single-crystal to single-crystal (SC-SC) hydrogenation of appropriate diene precursors forms the corresponding σ-alkane complexes [Rh(CyP(CH) PCy)(L)][BAr] ( n = 3, 4) and [ RhH(CyP(CH)( CH)(CH)PCy)(L)][BAr] ( n = 5, L = norbornane, NBA; cyclooctane, COA). Their structures, as determined by single-crystal X-ray diffraction, have cations exhibiting Rh···H-C σ-interactions which are modulated by both the chelating ligand and the identity of the alkane, while all sit in an octahedral anion microenvironment. These range from chelating η,η Rh···H-C (e.g., [Rh(CyP(CH) PCy)(ηη-NBA)][BAr], n = 3 and 4), through to more weakly bound η Rh···H-C in which C-H activation of the chelate backbone has also occurred (e.g., [ RhH(CyP(CH)( CH)(CH)PCy)(η-COA)][BAr]) and ultimately to systems where the alkane is not ligated with the metal center, but sits encapsulated in the supporting anion microenvironment, [Rh(CyP(CH)PCy)][COA⊂BAr], in which the metal center instead forms two intramolecular agostic η Rh···H-C interactions with the phosphine cyclohexyl groups. CHCl adducts formed by displacement of the η-alkanes in solution ( n = 5; L = NBA, COA), [ RhH(CyP(CH)( CH)(CH)PCy)(κ-ClCHCl)][BAr], are characterized crystallographically. Analyses via periodic DFT, QTAIM, NBO, and NCI calculations, alongside variable temperature solid-state NMR spectroscopy, provide snapshots marking the onset of Rh···alkane interactions along a C-H activation trajectory. These are negligible in [Rh(CyP(CH)PCy)][COA⊂BAr]; in [ RhH(CyP(CH)( CH)(CH)PCy)(η-COA)][BAr], σ → Rh σ-donation is supported by Rh → σ* "pregostic" donation, and in [Rh(CyP(CH) PCy)(ηη-NBA)][BAr] ( n = 2-4), σ-donation dominates, supported by classical Rh(dπ) → σ* π-back-donation. Dispersive interactions with the [BAr] anions and Cy substituents further stabilize the alkanes within the binding pocket.
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http://dx.doi.org/10.1021/jacs.8b09364DOI Listing
November 2018