Fluorometabolite biosynthesis : isotopically labelled glycerol incorporations into the antibiotic nucleocidin in Streptomyces calvus

Deuterium and carbon-13 labelled glycerols have been fed to Streptomyces calvus fermentations and isotope incorporation into the fluorine containing antibiotic nucleocidin have been evaluated by 19F-NMR. A single deuterium atom was incorporated from [2H5]- and (R)-[2H2]- glycerol into C-5’ of the antibiotic, suggesting that an oxidation occurs at this carbon after ribose ring assembly from glycerol (pentose phosphate pathway), during nucleocidin biosynthesis.PostprintPostprintPeer reviewe

Incorporation of [2H1]-(1R,2R)- and [2H1]-(1S,2R)-glycerols into the antibiotic nucleocidin in Streptomyces calvus

The authors thank the Chinese Scholarship Council for Ph.D Studentship support (to XF).Deuterium incorporations from [2H1]-(1R,2R) and [2H1]-(1S,2R) glycerols into the fluorine containing antibiotic nucleocidin, in Streptomyces calvus indicate that one deuterium atom is incorporated at the C-5′ site of nucleocidin from each of these isotopomers of glycerol. Two deuteriums become incorporated at C-5′ of nucleocidin after a feeding experiment with [2H5]-glycerol. These observations indicate that there is no obligate oxidation of the pro-R hydroxymethyl group of glycerol as it progresses through the pentose phosphate pathway and becomes incorporated into the fluorinated antibiotic.PostprintPeer reviewe

Measurements of neutron emission induced by muons stopped in metal deuteride targets

An 80 MeV/c negative muon beam from the Alternating Gradient Synchrotron at Brookhaven National Laboratory was used to investigate the stopping of muons inside Pd, Ti and Y targets saturated with deuterium. Neutron emission from the targets was measured with an array of {sup 3}He detectors, and in some runs, the temperature of the target was monitored as a function of time, with and without a flux of muons on the target. The neutron rates were also measured for Pd cathodes in an active electrochemical cell similar in design to those used in so-called cold-fusion'' experiments, and the electrolyte solution was analyzed for excess tritium at rates consistent with these claimed in cold fusion'' experiments. Neutron production catalyzed fusion due to the presence of deuterium in palladium deuteride, PdD{sub 0.7}, exposed to muons was determined in palladium 0.0 {plus minus} 0.03 (stat.) {plus minus} 0.25 (syst.) neutrons per stored muon. 15 refs., 5 figs

The economic costs of alcohol consumption in Thailand, 2006

<p>Abstract</p> <p>Background</p> <p>There is evidence that the adverse consequences of alcohol impose a substantial economic burden on societies worldwide. Given the lack of generalizability of study results across different settings, many attempts have been made to estimate the economic costs of alcohol for various settings; however, these have mostly been confined to industrialized countries. To our knowledge, there are a very limited number of well-designed studies which estimate the economic costs of alcohol consumption in developing countries, including Thailand. Therefore, this study aims to estimate these economic costs, in Thailand, 2006.</p> <p>Methods</p> <p>This is a prevalence-based, cost-of-illness study. The estimated costs in this study included both direct and indirect costs. Direct costs included health care costs, costs of law enforcement, and costs of property damage due to road-traffic accidents. Indirect costs included costs of productivity loss due to premature mortality, and costs of reduced productivity due to absenteeism and presenteeism (reduced on-the-job productivity).</p> <p>Results</p> <p>The total economic cost of alcohol consumption in Thailand in 2006 was estimated at 156,105.4 million baht (9,627 million US$PPP) or about 1.99$ PPP), followed by cost of productivity loss due to reduced productivity (45,464.6 million baht/2,804 million US$PPP), health care cost (5,491.2 million baht/339 million US$ PPP), cost of property damage as a result of road traffic accidents (779.4 million baht/48 million US$PPP), and cost of law enforcement (242.4 million baht/15 million US$ PPP), respectively. The results from the sensitivity analysis revealed that the cost ranges from 115,160.4 million baht to 214,053.0 million baht (7,102.1 - 13,201 million US$ PPP) depending on the methods and assumptions employed.</p> <p>Conclusions</p> <p>Alcohol imposes a substantial economic burden on Thai society, and according to these findings, the Thai government needs to pay significantly more attention to implementing more effective alcohol policies/interventions in order to reduce the negative consequences associated with alcohol.</p

Outcomes from elective colorectal cancer surgery during the SARS-CoV-2 pandemic

This study aimed to describe the change in surgical practice and the impact of SARS-CoV-2 on mortality after surgical resection of colorectal cancer during the initial phases of the SARS-CoV-2 pandemic

Manganese-Porphyrin-Catalyzed C-H Fluorination: Hydrocarbons, But Not Drugs?

Transformation of C-H to C-F bonds in organic compounds can be used in drug design to easily diversify molecular series under exploration. A particularly attractive fluorination reaction is the recently discovered aliphatic C-H bonds fluorination catalyzed by manganese(Mn)-containing porphyrins, which proceeds under mild conditions and with high yields. However, this fluorination technique has been applied so far only to a narrow range of carbon rich organic substrates. In this preliminary study, based on quantum chemical modeling of several key stages in the presumed mechanism of this reaction, we put forward a hypothesis to explain difficulties of extending the Mn-porphyrin-catalyzed fluorination to nitrogen rich drug-like molecules, namely, a significant growth of the height of the activation barrier for drug-like substrates. Specifically, we demonstrate that reaction energies are comparable for various substrates, including those for which Mn-porphyrin-catalyzed fluorination occurs and those for which it does not occur, and hence, thermodynamic factors are unlikely to control the observed differences in the reactivity. Next, we carry out a first-pass modeling of fluorination reaction paths for two substrates, cyclohexane versus piperidine, as a representative of the type of nitrogen rich compound that can and cannot be fluorinated under recommended conditions, and found a significant difference in activation energies (~7 kcal/mol vs ~40 kcal/mol), which might point at the reason for the difference in the reactivity. Further computational modeling is required to reveal the limitations of the Mn-porphyrin-catalyzed fluorination, and, if possible, possible ways to overcome such limitations

Fluorometabolite biosynthesis:isotopically labelled glycerol incorporations into the antibiotic nucleocidin in <i>Streptomyces calvus</i>

Deuterium and carbon-13 labelled glycerols have been fed to Streptomyces calvus fermentations and isotope incorporation into the fluorine containing antibiotic nucleocidin have been evaluated by 19F-NMR. A single deuterium atom was incorporated from [2H5]- and (R)-[2H2]- glycerol into C-5’ of the antibiotic, suggesting that an oxidation occurs at this carbon after ribose ring assembly from glycerol (pentose phosphate pathway), during nucleocidin biosynthesis

Incorporation of [²H₁]-(1R,2R)- and [²H₁]-(1S,2R)-glycerols into the antibiotic nucleocidin in <i>Streptomyces calvus</i>

Deuterium incorporations from [2H1]-(1R,2R) and [2H1]-(1S,2R) glycerols into the fluorine containing antibiotic nucleocidin, in Streptomyces calvus indicate that one deuterium atom is incorporated at the C-5′ site of nucleocidin from each of these isotopomers of glycerol. Two deuteriums become incorporated at C-5′ of nucleocidin after a feeding experiment with [2H5]-glycerol. These observations indicate that there is no obligate oxidation of the pro-R hydroxymethyl group of glycerol as it progresses through the pentose phosphate pathway and becomes incorporated into the fluorinated antibiotic

Predictive Minisci late stage functionalization with transfer learning.

Acknowledgements: Financial support for this work was generously provided by Pfizer and the Royal Society (Newton International Fellowship to E.K.S. and University Research Fellowship to A.A.L.). We wish to thank Rokas Elijošius, William McCorkindale, and Oliver P. King-Smith for their enlightening discussions. We are grateful to Hans Renata and Roger M. Howard for assistance in manuscript preparation. The authors would like to acknowledge several Pfizer colleagues and Spectrix vendor partners who have contributed to this work including Manjinder Lall, Gregory Walker, R. Scott Obach, and Douglas Spracklin for their leadership and execution of the Lead Diversification Platform (LDP), and Danial Morris for LDP product generation, isolations, bioanalytical support, and anyone else who has contributed to the LDP from the date of its inception.Funder: Royal Society; doi: https://doi.org/10.13039/501100000288Funder: Pfizer (Pfizer Inc.); doi: https://doi.org/10.13039/100004319Funder: Spectrix Analytical LLCStructural diversification of lead molecules is a key component of drug discovery to explore chemical space. Late-stage functionalizations (LSFs) are versatile methodologies capable of installing functional handles on richly decorated intermediates to deliver numerous diverse products in a single reaction. Predicting the regioselectivity of LSF is still an open challenge in the field. Numerous efforts from chemoinformatics and machine learning (ML) groups have made strides in this area. However, it is arduous to isolate and characterize the multitude of LSF products generated, limiting available data and hindering pure ML approaches. We report the development of an approach that combines a message passing neural network and 13C NMR-based transfer learning to predict the atom-wise probabilities of functionalization for Minisci and P450-based functionalizations. We validated our model both retrospectively and with a series of prospective experiments, showing that it accurately predicts the outcomes of Minisci-type and P450 transformations and outperforms the well-established Fukui-based reactivity indices and other machine learning reactivity-based algorithms

Predictive Minisci and P450 Late Stage Functionalization with Transfer Learning

Structural diversification of lead molecules is a key component of drug discovery to explore chemical space. Late stage functionalizations (LSFs) are versatile methodologies capable of installing functional handles on richly decorated intermediates to deliver numerous diverse products in a single reaction. Predicting the regioselectivity of LSF is still an open challenge in the field. Numerous efforts from chemoinformatics and machine learning (ML) groups have made significant strides in this area. However, it is arduous to isolate and characterize the multitude of LSF products generated, limiting available data and hindering pure ML approaches. We report the development of an approach that combines a message passing neural network and 13C NMR-based transfer learning to predict the atom-wise probabilities of functionalization for Minisci and P450-based functionalizations. We validated our model both retrospectively and with a series of prospective experiments, showing that it accurately predicts the outcomes of Minisci-type and P450 transformations and outperforms the well-established Fukui-based reactivity indices and other machine learning reactivity-based algorithms