Mark David Lim, Ph.D. PMP

Randomized clinical trials are underway to evaluate the efficacy of novel agents targeting the alternative complement pathway in patients with C3G, a rare glomerular disease. The Kidney Health Initiative (KHI) convened a panel of experts in C3G to: (1) assess the data supporting the use of the prespecified trial endpoints as measures of clinical benefit; and (2) opine on efficacy findings they would consider compelling as treatment(s) for C3G in native kidneys. Two subpanels of the C3G Trial… Show more

Randomized clinical trials are underway to evaluate the efficacy of novel agents targeting the alternative complement pathway in patients with C3G, a rare glomerular disease. The Kidney Health Initiative (KHI) convened a panel of experts in C3G to: (1) assess the data supporting the use of the prespecified trial endpoints as measures of clinical benefit; and (2) opine on efficacy findings they would consider compelling as treatment(s) for C3G in native kidneys. Two subpanels of the C3G Trial Endpoints Work group reviewed the available evidence and uncertainties for the association between the three prespecified endpoints -- (1) proteinuria; (2) estimated glomerular filtration rate (eGFR); and (3) histopathology -- and anticipated outcomes. The full work group provided feedback on the summaries provided by the subpanels and on what potential treatment effects on the proposed endpoints they would consider compelling to support evidence of an investigational product's effectiveness for treating C3G. Members of the full work group agreed with the characterization of the data, the evidence, and uncertainties, supporting the endpoints. Given the limitations of the available data, the workgroup was unable to define a minimum threshold for change in any of the endpoints that might be considered clinically meaningful. The workgroup concluded that a favorable treatment effect on all three endpoints would provide convincing evidence of efficacy in the setting of a therapy that targeted the complement pathway. A therapy might be considered effective in the absence of complete alignment in all three endpoints if there was meaningful lowering of proteinuria and stabilization or improvement in eGFR. The panel unanimously supported efforts to foster data sharing between academic and industry partners to address the gaps in the current knowledge identified by the review of the endpoints in the aforementioned trials. Show less

Perspective on the why and the how input from families and people with kidney diseases is essential for biomedical product development.

Although preventive chemotherapy has been instrumental in reducing schistosomiasis incidence worldwide, serious challenges remain. These problems include the omission of certain groups from campaigns of mass drug administration, the existence of persistent disease hotspots, and the risk of recrudescent infections. Central to these challenges is the fact that the diagnostic tools currently used to establish the burden of infection are not sensitive enough, especially in low-endemic settings… Show more

Although preventive chemotherapy has been instrumental in reducing schistosomiasis incidence worldwide, serious challenges remain. These problems include the omission of certain groups from campaigns of mass drug administration, the existence of persistent disease hotspots, and the risk of recrudescent infections. Central to these challenges is the fact that the diagnostic tools currently used to establish the burden of infection are not sensitive enough, especially in low-endemic settings, which results in underestimation of the true prevalence of active Schistosoma spp infections. This central issue necessitates that the current schistosomiasis control strategies recommended by WHO are re-evaluated and, possibly, adapted. More targeted interventions and novel approaches have been used to estimate the prevalence of schistosomiasis, such as establishing infection burden by use of precision mapping, which provides high resolution spatial information that delineates variations in prevalence within a defined geographical area. Such information is instrumental in guiding targeted intervention campaigns. However, the need for highly accurate diagnostic tools in such strategies is a crucial factor that is often neglected. The availability of highly sensitive diagnostic tests also opens up the possibility of applying strategies of sample pooling to reduce the cost of control programmes. To interrupt the transmission of, and eventually eliminate, schistosomiasis, better local targeting of preventive chemotherapy, in combination with highly sensitive diagnostic tools, is crucial. Show less

A review of the literature on the feasibility of dried blood spots for remote diagnostics

Diagnostics play a critical role in guiding both the deployment of existing STH program resources and the implementation and evaluation of STH intervention strategies. Currently used coproscopic methods to detect and quantify STH-specific eggs, such as the Kato-Katz method, have practical advantages; test kits are inexpensive and relatively easy to perform in low-resourced field settings. They also have significant disadvantages, including moderate labor costs, lower than optimal sensitivity… Show more

Diagnostics play a critical role in guiding both the deployment of existing STH program resources and the implementation and evaluation of STH intervention strategies. Currently used coproscopic methods to detect and quantify STH-specific eggs, such as the Kato-Katz method, have practical advantages; test kits are inexpensive and relatively easy to perform in low-resourced field settings. They also have significant disadvantages, including moderate labor costs, lower than optimal sensitivity, and poor reproducibility in most program settings. Several academic and small-business efforts continue to develop tools with improved diagnostic performance. However, an objective assessment on the value proposition offered by these tools has been complicated, as the diagnostic needs of a multiphased STH program have not been defined.

This report shares a user-centered framework developed by a diverse group of key opinion leaders convened over the past year by the Bill & Melinda Gates Foundation to define circumstances in which population-level diagnostic data could guide an STH program manager’s decision to transition a program to the next phase. The use-cases and companion target product profiles (TPPs) are intended to provide the community with a pathway for the research, development, evaluation, and implementation of diagnostic tools designed for STH programs. This framework can also be used to prioritize research or product development resources based on immediate and anticipated program needs. Show less

Carnitines are diagnostic biomarkers of fatty acid oxidation defects and organic acidemias. Quantitative measurements of various carnitines in dried blood spot (DBS) have potential use in remote health applications for disease diagnosis and epidemiological surveillance. To provide an improved LC/multiple-reaction monitoring (MRM)-MS method for quantitation of carnitines in DBS, 3-nitrophenylhydrazine (3NPH) was tested as a high-efficiency chemical isotope-labeling reagent for pre-analytical… Show more

Carnitines are diagnostic biomarkers of fatty acid oxidation defects and organic acidemias. Quantitative measurements of various carnitines in dried blood spot (DBS) have potential use in remote health applications for disease diagnosis and epidemiological surveillance. To provide an improved LC/multiple-reaction monitoring (MRM)-MS method for quantitation of carnitines in DBS, 3-nitrophenylhydrazine (3NPH) was tested as a high-efficiency chemical isotope-labeling reagent for pre-analytical derivatization of 24 routinely-analyzed species. Show less

Included as part of book, "Diagnostic Devices with Microfluidics" edited by Francesco Piraino, Šeila Selimović. The chapter focuses on how to start with the diagnostic use-case to define end-user needs, as the first step for developing any new diagnostic technology.

Article written in issue on "quenching epidemics" within an industry journal directed at the intelligence community's investment and technology development stakeholders. This article highlights many of the challenges when using human specimens for molecular analysis (research, clinical, etc).

Recent years have witnessed the establishment of over 400 consortia to translate biomedical research advances into new therapies for major unmet needs, such as brain disorders, antimicrobial resistance, diabetes, immune-inflammatory diseases and cancer1. These consortia typically bring together multiple stakeholders, including large and small-sized companies, academic research institutions, public health organizations, regulatory agencies and patient groups. The rationale behind these efforts… Show more

Recent years have witnessed the establishment of over 400 consortia to translate biomedical research advances into new therapies for major unmet needs, such as brain disorders, antimicrobial resistance, diabetes, immune-inflammatory diseases and cancer1. These consortia typically bring together multiple stakeholders, including large and small-sized companies, academic research institutions, public health organizations, regulatory agencies and patient groups. The rationale behind these efforts, many of which are public-private partnerships, is to assemble a critical mass of expertise and resources that can not only solve highly complex challenges of drug discovery and development but also ensure that scientific breakthroughs are exploited by the pharmaceutical industry and regulatory agencies to benefit patients and society. The establishment of public-private consortia is usually based on the definition of a 'precompetitive' space in which private companies agree to share knowledge, investment and risk. One way to measure the performance of such consortia is to use the scientific literature—bibliometrics—as a means for assessing the output and/or quality of partnerships for health innovation. Here, we study the scientific output of the archetypal European precompetitive consortium: the Innovative Medicines Initiative Show less

Disease-focused philanthropic organizations play an increasing role in the strategy and conduct of biomedical research, with many focusing on drug development for specific diseases and patients populations. More and more they not only provide resources and expertise, but also take active part managing the strategy and objectives of targeted research programs, an approach known as venture philanthropy. Many also lead and participate in public-private partnerships. One example is the partnership… Show more

Disease-focused philanthropic organizations play an increasing role in the strategy and conduct of biomedical research, with many focusing on drug development for specific diseases and patients populations. More and more they not only provide resources and expertise, but also take active part managing the strategy and objectives of targeted research programs, an approach known as venture philanthropy. Many also lead and participate in public-private partnerships. One example is the partnership between the Polycystic Kidney Disease Foundation (PKD) and the Critical Path Institute which brings several pharmaceutical companies and academic institutions to develop new broadly-used biomarkers. Another case is the partnership between JDRF (formerly known as the Juvenile Diabetes Research foundation) and the Innovative Medicines Initiative (IMI), involving a financial support of the IMIDIA project (Innovative Medicines Initiative for Diabetes) which is focused on improving beta-cell function and identifying biomarkers for diabetes treatment monitoring. These examples show that in addition to providing financial support and expertise, philanthropic foundations may be in a unique position to coordinate the patient and research communities for specific medicines development projects. Show less

Some common challenges of biomedical product translation—scientific, regulatory, adoption, and reimbursement—can best be addressed by the broad sharing of resources or tools. But, such aids remain undeveloped because the undertaking requires expertise from multiple research sectors as well as validation across organizations. Biomedical resource development can benefit from directed consortia—a partnership framework that provides neutral and temporary collaborative environments for several… Show more

Some common challenges of biomedical product translation—scientific, regulatory, adoption, and reimbursement—can best be addressed by the broad sharing of resources or tools. But, such aids remain undeveloped because the undertaking requires expertise from multiple research sectors as well as validation across organizations. Biomedical resource development can benefit from directed consortia—a partnership framework that provides neutral and temporary collaborative environments for several, oftentimes competing, organizations and leverages the aggregated intellect and resources of stakeholders so as to create versatile solutions. By analyzing 369 biomedical research consortia, we tracked consortia growth around the world and gained insight into how this partnership model advances biomedical research. Our analyses suggest that research-by-consortium provides benefit to biomedical science, but the model needs further optimization before it can be fully integrated into the biomedical research pipeline. Show less

High-quality biospecimens with appropriate clinical annotation are critical in the era of personalized medicine. It is now widely recognized that biospecimen resources need to be developed and operated under established scientific, technical, business, and ethical/legal standards. To date, such standards have not been widely practiced, resulting in variable biospecimen quality that may compromise research efforts. The National Cancer Institute (NCI) Office of Biorepositories and Biospecimen… Show more

High-quality biospecimens with appropriate clinical annotation are critical in the era of personalized medicine. It is now widely recognized that biospecimen resources need to be developed and operated under established scientific, technical, business, and ethical/legal standards. To date, such standards have not been widely practiced, resulting in variable biospecimen quality that may compromise research efforts. The National Cancer Institute (NCI) Office of Biorepositories and Biospecimen Research (OBBR) was established in 2005 to coordinate NCI’s biospecimen resource activities and address those issues that affect access to the high-quality specimens and data necessary for its research enterprises as well as the broader translational research field. OBBR and the NCI Biorepository Coordinating Committee developed NCI’s “Best Practices for Biospecimen Resources” after consultation with a broad array of experts. A Biospecimen Research Network was established to fund research to develop additional evidence-based practices. Although these initiatives will improve the overall availability of high-quality specimens and data for cancer research, OBBR has been authorized to implement a national biobanking effort, cancer HUman Biobank (caHUB). caHUB will address systematically the gaps in knowledge needed to improve the state-of-the-science and strengthen the standards for human biobanking. This commentary outlines the progressive efforts by NCI in technical, governance, and economic considerations that will be important as the new caHUB enterprise is undertaken. Show less

Personalized medicine requires capabilities to detect and measure health-associated biomarkers with increasingly specific and sensitive methods, putting analytical chemists at the front lines of translational research. Analytical scientists must be upstream in the experimental design process because the analysis of a biospecimen (tissue, blood, etc.) presents technical and experimental design complexities.

Photolysis of the nitrato chromium(III) tetraphenylporphyrinato compound Cr(TPP)(NO3) (TPP, tetraphenylporphyrin) in toluene solution clearly leads to the formation of the Cr(IV) oxo complex Cr(TPP)(O) with a quantum yield of 0.011. The other product, NO2, was detected quantitatively by its reaction with the spin trapping agent 2,2,6,6-tetramethyl-piperidine-1-oxyl.

The pace of biomedical research towards reducing the onset of disease is greatly accelerated when out-of-thebox approaches are used to develop a novel technology and tool. The National Cancer Institute's program for Innovative Molecular Analysis Technologies (IMAT) continues to focus on supporting and stimulating investigator-initiated innovation to develop technologies that have the potential for revolutionizing cancer research and care. Also described in this extended abstract are other… Show more

The pace of biomedical research towards reducing the onset of disease is greatly accelerated when out-of-thebox approaches are used to develop a novel technology and tool. The National Cancer Institute's program for Innovative Molecular Analysis Technologies (IMAT) continues to focus on supporting and stimulating investigator-initiated innovation to develop technologies that have the potential for revolutionizing cancer research and care. Also described in this extended abstract are other funding opportunities from the National Institutes of Health (NIH) that may be of interest to those seeking support for technology development. Show less

This report details the proceedings of the 2009 Biospecimen Research Network (BRN) Symposium that took place on March 16 to 18, 2009, the second in a series of annual symposia sponsored by the National Cancer Institute Office of Biorepositories and Biospecimen Research. The BRN Symposium is a public forum addressing the relevance of biospecimen quality to progress in cancer research and the systematic investigation needed to understand how different methods of collection, processing, and… Show more

This report details the proceedings of the 2009 Biospecimen Research Network (BRN) Symposium that took place on March 16 to 18, 2009, the second in a series of annual symposia sponsored by the National Cancer Institute Office of Biorepositories and Biospecimen Research. The BRN Symposium is a public forum addressing the relevance of biospecimen quality to progress in cancer research and the systematic investigation needed to understand how different methods of collection, processing, and storage of human biospecimens affect subsequent molecular research results. More than 300 participants from industry, academia, and government attended the symposium, which featured both formal presentations and a day of workshops aimed at addressing several key issues in biospecimen science. An additional 100 individuals participated via a live webcast (archived at http://brnsymposium.com). The BRN Symposium is part of a larger program designed as a networked, multidisciplinary research approach to increase the knowledge base for biospecimen science. Biospecimens are generally understood to represent an accurate representation of a patient's disease biology, but can instead reflect a combination of disease biology and the biospecimen's response to a wide range of biological stresses. The molecular signatures of disease can thus be confounded by the signatures of biospecimen biological stress, with the potential to affect clinical and research outcomes through incorrect diagnosis of disease, improper use of a given therapy, and irreproducible research results that can lead to misinterpretation of artifacts as biomarkers. Biospecimen research represents the kind of bricks-and-mortar research that provides a solid scientific foundation for future advances that will directly help patients Show less

Proteases are a family of naturally occurring enzymes in the body whose dysregulation has been implicated in numerous diseases and cancers. Their ability to selectively and catalytically turnover substrate adds both signal amplification and functionality as parameters for the detection of disease. This review will focus on the development of activity-based methodologies to characterize proteases, and in particular, the use of positional scanning, synthetic combinatorial libraries (PS-SCL's)… Show more

Proteases are a family of naturally occurring enzymes in the body whose dysregulation has been implicated in numerous diseases and cancers. Their ability to selectively and catalytically turnover substrate adds both signal amplification and functionality as parameters for the detection of disease. This review will focus on the development of activity-based methodologies to characterize proteases, and in particular, the use of positional scanning, synthetic combinatorial libraries (PS-SCL's), and substrate activity screening (SAS) assays. The use of these approaches to better understand a protease's natural substrate will be discussed as well as the technologies that emerged. Show less

The declining value of the dollar and the evolving shape of the economy are affecting the value and availability of the funds that support the development and commercialization of novel cancer technologies. This conservatism goes against the forward advance of translational science, which is beginning to show its greatest promise for the pursuit of innovation and the dissemination of emerging technologies. Cancer technology development is nearing a tipping point in which these countering trends… Show more

The declining value of the dollar and the evolving shape of the economy are affecting the value and availability of the funds that support the development and commercialization of novel cancer technologies. This conservatism goes against the forward advance of translational science, which is beginning to show its greatest promise for the pursuit of innovation and the dissemination of emerging technologies. Cancer technology development is nearing a tipping point in which these countering trends may result in a decline of the United States' ability to encourage and foster innovation. The National Cancer Institute's Innovative Molecular Analysis Technologies (IMAT) program is attempting to address this rapidly changing environment to ensure that innovation is not stifled. Discussed is an overview of the IMAT program, identified bottlenecks for innovation, and a proposed strategy for engaging new partners to strengthen the pipeline for innovative cancer technologies. Show less

We report the use of a SiN x based gold coated microcantilever array to quantitatively measure the activity and inhibition of a model protease immobilized on its surface. Trypsin was covalently bound to the gold surface of the microcantilever using a synthetic spacer, and the remaining exposed silicon nitride surface was passivated with silanated polyethylene glycol. The nanoscale cantilever motions induced by trypsin during substrate turnover were quantitatively measured using an optical… Show more

We report the use of a SiN x based gold coated microcantilever array to quantitatively measure the activity and inhibition of a model protease immobilized on its surface. Trypsin was covalently bound to the gold surface of the microcantilever using a synthetic spacer, and the remaining exposed silicon nitride surface was passivated with silanated polyethylene glycol. The nanoscale cantilever motions induced by trypsin during substrate turnover were quantitatively measured using an optical laser-deflection technique. These microcantilever deflections directly correlated with the degree of protease turnover of excess synthetic fibronectin substrate ( K M = 0.58 x 10 (-6) M). Inhibition of surface-immobilized trypsin by soybean trypsin inhibitor (SBTI) was also observed using this system. Show less

In this chapter, we will discuss the mechanistic studies of NO and NOxView the MathML source(NO2−, ⋅NO2,N2O3, etc.) reactions with heme proteins and heme model compounds, with the goal of providing further insight into the related reactions occurring in mammalian biology.

Ion mobility mass spectrometry (IM-MS) was used to probe the structures of several metal complexes carrying pendant chromophores. The three complexes investigated were the copper(II) complex Cu(DAC)2+ (DAC = 1,8-bis(9-methylanthracyl)cyclam, cyclam = 1,4,8,11-tetraazacyclotetradecane), the N-nitrosylated ligand DAC-NO, and the Roussin's red salt ester (μ-S,μ-S‘)-protoporphyrin-IX-bis(2-thioethyl ester)tetranitrosyldiiron (PPIX-RSE). From the IM-MS data coupled with theoretical calculations, it… Show more

Ion mobility mass spectrometry (IM-MS) was used to probe the structures of several metal complexes carrying pendant chromophores. The three complexes investigated were the copper(II) complex Cu(DAC)2+ (DAC = 1,8-bis(9-methylanthracyl)cyclam, cyclam = 1,4,8,11-tetraazacyclotetradecane), the N-nitrosylated ligand DAC-NO, and the Roussin's red salt ester (μ-S,μ-S‘)-protoporphyrin-IX-bis(2-thioethyl ester)tetranitrosyldiiron (PPIX-RSE). From the IM-MS data coupled with theoretical calculations, it was found that [CuII(DAC − H)]+ exists as a single conformer, with one anthracenyl group above the cyclam and the other below, similar to the crystal structure of CuII(DAC)2+. The metal-free N-nitrosylated ligand (DAC-NO + H)+ has two conformations:  one family of structures has one anthracenyl group above the cyclam and one below, while the other has both anthracenyl groups on the same side of the cyclam. These observations are consistent with 1H NMR data for the neutral DAC-NO complex that indicate the presence of two geometric isomers in solution. The third species, PPIX-RSE, has a porphyrin chromophore covalently linked to an Fe2S2(NO)4 cluster for use as a precursor for the photochemical delivery of nitric oxide in single- and two-photon excitation processes. Ion mobility indicates the presence of two (PPIX-RSE + H)+ conformations, consistent with the previous interpretation of the bimodal fluorescence lifetime decay seen for PPIX-RSE. DFT structures, in good agreement with the IM-MS cross sections, indicate two “bent” conformations with the planes of the porphyrin and Fe2S2 rings at different angles with respect to each other. Show less

The reactions of nitric oxide (NO) have been a subject of broad interest among biochemists and chemists. This report discusses several quantitative techniques to handle and use NO gas that has been delivered from compressed cylinders. The focus is on techniques that minimize and avoid the presence of oxygen impurities, which when present, result in the generation of other nitrogen oxides (NOx). These NOx species typically exhibit different reactivity, and unless removed or quantified, their… Show more

The reactions of nitric oxide (NO) have been a subject of broad interest among biochemists and chemists. This report discusses several quantitative techniques to handle and use NO gas that has been delivered from compressed cylinders. The focus is on techniques that minimize and avoid the presence of oxygen impurities, which when present, result in the generation of other nitrogen oxides (NOx). These NOx species typically exhibit different reactivity, and unless removed or quantified, their presence will complicate studies focusing on the reactions caused by NO itself. Show less

Described are further studies directed towards elucidating the mechanism of the nitric oxide reduction of the copper(II) model system, Cu(dmp)22+ (I, dmp = 2,9-dimethyl-1,10-phenanthroline). The reaction of I with NO in methanol results in the formation of Cu(dmp)2+ (II) and methyl nitrite (CH3ONO), with a second order rate constant kNO = 38.1 M−1 s−1 (298 K). The activation parameters for this reaction in buffered aqueous medium were measured to be ΔH‡ = 41.6 kJ/mol and ΔS‡ = −82.7 kJ/mol deg.… Show more

Described are further studies directed towards elucidating the mechanism of the nitric oxide reduction of the copper(II) model system, Cu(dmp)22+ (I, dmp = 2,9-dimethyl-1,10-phenanthroline). The reaction of I with NO in methanol results in the formation of Cu(dmp)2+ (II) and methyl nitrite (CH3ONO), with a second order rate constant kNO = 38.1 M−1 s−1 (298 K). The activation parameters for this reaction in buffered aqueous medium were measured to be ΔH‡ = 41.6 kJ/mol and ΔS‡ = −82.7 kJ/mol deg. The addition of azide ion (N3−) as a competing nucleophile results in a marked acceleration in the rate of the copper(II) reduction. Analysis of the kinetics for the NO reduction of the bulkier Cu(dpp)22+ (IV, dpp = 2,9-diphenyl-1,10-phenanthroline) and the stronger oxidant, Cu (NO2-dmp)22+ (V, NO2-dmp = 5-nitro-2,9-dimethyl-1,10-phenanthroline), gave the second order rate constants kNO = 21.2 and 29.3 M−1 s−1, respectively. These results argue against an outer sphere electron transfer pathway and support a mechanism where the first step involves the formation of a copper–nitrosyl (Cu(II)–NO or Cu(I)–NO+) adduct. This would be followed by the nucleophilic attack on the bound NO and the labilization of RONO to form the nitrite products and the cuprous complex. Show less

The reaction(s) of nitric oxide (nitrogen monoxide) gas with sublimed layers containing the nitrato iron(III) complex FeIII(TPP)(η2-O2NO) (1, TPP = meso-tetraphenyl porphyrinate2-) leads to formation of several iron porphyrin species that are ligated by various nitrogen oxides. The eventual products of these low-temperature solid-state reactions are the nitrosyl complex Fe(TPP)(NO), the nitro-nitrosyl complex Fe(TPP)(NO2)(NO), and 1 itself, and the relative final quantities of these were… Show more

The reaction(s) of nitric oxide (nitrogen monoxide) gas with sublimed layers containing the nitrato iron(III) complex FeIII(TPP)(η2-O2NO) (1, TPP = meso-tetraphenyl porphyrinate2-) leads to formation of several iron porphyrin species that are ligated by various nitrogen oxides. The eventual products of these low-temperature solid-state reactions are the nitrosyl complex Fe(TPP)(NO), the nitro-nitrosyl complex Fe(TPP)(NO2)(NO), and 1 itself, and the relative final quantities of these were functions of the NO partial pressure. It is particularly notable that isotope labeling experiments show that the nitrato product is not simply unreacted 1 but is the result of a series of transformations taking place in the layered material. Thus, the nitrato complex formed from solid Fe(TPP)(η2-O2NO) maintained under a 15NO atmosphere was found to be the labeled analogue Fe(TPP)(η2-O215NO). The reactivities of the layered solids are compared to the behaviors of the same species in ambient temperature solutions. To interpret the reactions of the labeled nitrogen oxides, the potential exchange reactions between N2O3 and 15NO were examined, and complete isotope scrambling was observed between these species under the reaction conditions (T = 140 K). Overall it was concluded from isotope labeling experiments that the sequence of reactions is initiated by reaction of 1 with NO to give the nitrato nitrosyl complex Fe(TPP)(η1-ONO2)(NO) (2) as an intermediate. This is followed by a reaction in the presence of excess NO that is equivalent to the loss of the nitrate radical NO3•to give Fe(TPP)(NO) as another transient species. A plausible pathway involving NO attack on the coordinated nitrate of 2 resulting in the release of N2O4 concerted with electron transfer to the metal center is proposed. Show less

A novel cyclic tetra-nuclear dinitrosyl iron complex [Fe(NO)2(Im-H)]4 was isolated and characterized by X-ray crystallography, and in donor solvents this fragments into 17 e- monomeric units that give EPR spectra analogous to the g= 2.03 species seen in mammalian biology.

There has been an ongoing interest in the reactions of nitric oxide (NO) with heme model compounds, with the goal of interpreting related reactions occurring in biology. With recent evidence that higher oxides (View the MathML source, radical dotNO2, N2O3, etc.) may also be formed under bioregulatory conditions, there is a need to understand the reactivities of these compounds with such models. This review discusses the mechanistic studies of the reactions of iron, ruthenium, and osmium… Show more

There has been an ongoing interest in the reactions of nitric oxide (NO) with heme model compounds, with the goal of interpreting related reactions occurring in biology. With recent evidence that higher oxides (View the MathML source, radical dotNO2, N2O3, etc.) may also be formed under bioregulatory conditions, there is a need to understand the reactivities of these compounds with such models. This review discusses the mechanistic studies of the reactions of iron, ruthenium, and osmium metalloporphyrin complexes with NO and the higher nitrogen oxides. Show less

The base-catalyzed reaction of nitric oxide with the Cu(II) complex Cu(DAC)2+ (DAC = 1,8-bis(9-anthracyl-methyl)-(1,4,8,11-tetraazacyclotetradecane)) leads to reduction of the metal center and the unexpected intramolecular nitrosylation of a secondary amine.

Described are studies directed toward elucidating the controversial chemistry relating to the solution phase reactions of nitric oxide with the iron(II) porphyrin complex Fe(TPP)(NO) (1, TPP = meso-tetraphenylporphinato2-). The only reaction observable with clean NO is the formation of the diamagnetic dinitrosyl species Fe(TPP)(NO)2 (2), and this is seen only at low temperatures (K1 < 3 M-1 at ambient temperature). However, 1 does readily react reversibly with N2O3 in the presence of excess… Show more

Described are studies directed toward elucidating the controversial chemistry relating to the solution phase reactions of nitric oxide with the iron(II) porphyrin complex Fe(TPP)(NO) (1, TPP = meso-tetraphenylporphinato2-). The only reaction observable with clean NO is the formation of the diamagnetic dinitrosyl species Fe(TPP)(NO)2 (2), and this is seen only at low temperatures (K1 < 3 M-1 at ambient temperature). However, 1 does readily react reversibly with N2O3 in the presence of excess NO to give the nitro nitrosyl complex Fe(TPP)(NO2)(NO) (3), suggesting that previous claims that 1 promotes NO disproportionation to give 3 may have been compromised by traces of air in the nitric oxide sources. It is also noted that 3 undergoes reversible loss of NO to give the elusive nitro species Fe(TPP)(NO2) (4), which has been implicated as a powerful oxygen atom transfer agent in reactions with various substrates. Furthermore, in the presence of excess NO2, the latter undergoes oxidation to the stable nitrato analogue Fe(TPP)(NO3) (5). Owing to such reactivity of Fe(TPP)(NO2), flash photolysis and stopped-flow kinetics rather than static techniques were necessary for the accurate measurement of dissociation equilibria characteristic of Fe(TPP)(NO2)(NO) in 298 K toluene solution. Flash photolysis of 3 resulted in competitive NO2 and NO dissociation to give Fe(TPP)(NO) and Fe(TPP)(NO2), respectively. The rate constant for the reaction of 1 with N2O3 to generate Fe(TPP)(NO2)(NO) was determined to be 1.8 × 106 M-1 s-1, and that for the NO reaction with 4 was similarly determined to be 4.2 × 105 M-1 s-1. Stopped-flow rapid dilution techniques were used to determine the rate constant for NO dissociation from 3 as 2.6 s-1. The rapid dilution experiments also demonstrated that Fe(TPP)(NO2) readily undergoes further oxidation to give Fe(TPP)(NO3). Show less

The oxidation of PPh3 by NO to N2O and Ph3PO in homogeneous solution occurs by third-order kinetics, d[Ph3P]/dt = k3[Ph3P][NO]2; analysis of solvent and substituent effects suggests formation of a phosphonium diazeniumdiolate intermediate prior to oxygen transfer from nitrogen to phosphorus.