Beyond iron: non-classical biological functions of bacterial siderophores

Bacteria secrete small molecules known as siderophores to acquire iron from their surroundings. For over 60 years, investigations into the bioinorganic chemistry of these molecules, including fundamental coordination chemistry studies, have provided insight into the crucial role that siderophores play in bacterial iron homeostasis. The importance of understanding the fundamental chemistry underlying bacterial life has been highlighted evermore in recent years because of the emergence of antibiotic-resistant bacteria and the need to prevent the global rise of these superbugs. Increasing reports of siderophores functioning in capacities other than iron transport have appeared recently, but reports of “non-classical” siderophore functions have long paralleled those of iron transport. One particular non-classical function of these iron chelators, namely antibiotic activity, was documented before the role of siderophores in iron transport was established. In this Perspective, we present an exposition of past and current work into non-classical functions of siderophores and highlight the directions in which we anticipate that this research is headed. Examples include the ability of siderophores to function as zincophores, chalkophores, and metallophores for a variety of other metals, sequester heavy metal toxins, transport boron, act as signalling molecules, regulate oxidative stress, and provide antibacterial activity.National Institutes of Health (U.S.) (R21 A1101784

Understanding and Improving Platinum Anticancer Drugs - Phenanthriplatin

Approximately half of all patients who receive anticancer chemotherapy are treated with a platinum drug. Despite the widespread use of these drugs, the only cure that can be claimed is that of testicular cancer following cisplatin treatment. This article reviews some of our recent work on phenanthriplatin, a cisplatin derivative in which a chloride ion is replaced by phenanthridine, and on one of its analogues, the previously reported pyriplatin. These cationic complexes form monofunctional adducts on DNA that do not significantly distort the duplex, yet efficiently block transcription. Cell-based assays reveal altered cellular uptake properties and a cancer cell-killing profile different from those of established platinum drugs. Mechanistic work, including a crystal structure analysis of platinum-modified DNA in the active site of RNA polymerase II, is discussed herein.National Cancer Institute (U.S.) (Grant CA034992)Misrock Foundation (Postdoctoral Fellowship

Anomaly Detection in the Molecular Structure of Gallium Arsenide Using Convolutional Neural Networks

This paper concerns the development of a machine learning tool to detect anomalies in the molecular structure of Gallium Arsenide. We employ a combination of a CNN and a PCA reconstruction to create the model, using real images taken with an electron microscope in training and testing. The methodology developed allows for the creation of a defect detection model, without any labeled images of defects being required for training. The model performed well on all tests under the established assumptions, allowing for reliable anomaly detection. To the best of our knowledge, such methods are not currently available in the open literature; thus, this work fills a gap in current capabilities

Oxidative halogenation of cisplatin and carboplatin: synthesis, spectroscopy, and crystal and molecular structures of Pt(IV) prodrugs

A series of Pt(IV) prodrugs has been obtained by oxidative halogenation of either cisplatin or carboplatin. Iodobenzene dichloride is a general reagent that cleanly provides prodrugs bearing axial chlorides without the need to prepare intervening Pt(IV) intermediates or handle chlorine gas. Elemental bromine and iodine afford Pt(IV) compounds as well, although in the case of the iodine-mediated oxidation of carboplatin, an amido-bridged Pt(IV) side product also formed. A detailed analysis of the changes in spectroscopic and structural parameters induced by varying the axial halide is presented. A number of recurring motifs are observed in the solid state structures of these compounds.National Cancer Institute (U.S.) (Grant CA034992

Managed delay for coronary artery bypass graft surgery: The experience at one Canadian center

AbstractObjectives. This study sought to assess the impact of delaying coronary artery bypass surgery at one Canadian academic tertiary referral center.Background. Universal access to medical services in Canada comes at the expense of waiting lists whose impact has been incompletely assessed.Methods. A prospective, observational study of all residents of Nova Scotia and Prince Edward Island accepted for bypass surgery between 1 April 1992 and 31 October 1992 was undertaken to determine 1) whether triage guidelines were being followed; and 2) the incidence of cardiac death, nonfatal myocardial infarction and worsening symptoms associated with delayed operation. The analysis had 90% power to detect a mortality rate of ≥3% (alpha 0.05).Results. Of 423 patients referred, 35% were triaged as urgent, 9.7% as semiurgent A, 39% as semiurgent B and 16.3% as elective, with no age or gender bias identified. Operation occurred at ≤1 week in 25%, ≤1 month in 47%, and >6 months in 1.4%. There were no nonfatal myocardial infarctions, but five cardiac deaths occurred (1.2%). Of 275 patients not initially classified as urgent, 12.4% required reclassification to higher priorities because of worsening symptoms: none had perioperative myocardial infarction or died. One in four patients queued longer than target waiting times. Only 4% of patients considered prioritization on the basis of medical need unfair, but 64% experienced at least moderate anxiety.Conclusions. This triage system equitably stratified patients to a queue. Deaths were rare and could not be attributed to the triage process. Patients with worsening clinical status were safely accommodated with earlier waiting times, but concerns remain regarding excessive waiting times and patient anxiety

A “Push–Pull” Stabilized Phosphinidene Supported by a Phosphine‐Functionalized β‐Diketiminato Ligand

The use of a bis(diphenyl)phosphine functionalized β‐diketiminato ligand, [HC{(CH$_{3}$)C}$_{2}${(ortho‐[P(C$_{6}$H$_{5}$)$_{2}$]$_{2}$C$_{6}$H$_{4}$)N}$_{2}$]$^{-}$ (PNac), as a support for germanium(II) and tin(II) chloride and phosphaketene compounds, is described. The conformational flexibility and hemilability of this unique ligand provide a versatile coordination environment that can accommodate the electronic needs of the ligated elements. For example, chloride abstraction from [(PNac)ECl] (E=Ge, Sn) affords the cationic germyliumylidene and stannyliumylidene species [(PNac)E]$^{+}$ in which the pendant phosphine arms associate more strongly with the Lewis acidic main group element centers, providing further electronic stabilization. In a similar fashion, chemical decarbonylation of the germanium phosphaketene [(PNac)Ge(PCO)] with tris(pentafluorophenyl)borane affords a “push–pull” stabilized phosphinidene in which one of the phosphine groups of the ligand backbone associates with the low valent phosphinidene center

A Breast Cancer Stem Cell-Selective, Mammospheres-Potent Osmium(VI) Nitrido Complex

The effect of a newly developed osmium(VI) nitrido complex, 1, on breast cancer stem cells (CSCs) is reported. The complex displays selective toxicity for HMLER breast cancer cells enriched with CD44-positive, CSC-like cells over the same cells having reduced CSC character. Remarkably, 1 also reduces the proportion of CSCs within a heterogeneous breast cancer cell population and irreversibly inhibits the formation of free-floating mammospheres to an extent similar to that of salinomycin, a natural product that targets CSCs. Detailed mechanistic studies reveal that in breast cancer cells 1 induces DNA damage and endoplasmic reticulum stress, the latter being responsible for the CSC selectivity. The anti-CSC properties of 1 provide a strong impetus for the development of new metal-based compounds to target CSCs and to treat chemotherapy-resistant and relapsed tumors.National Cancer Institute (U.S.) (Grant CA034992)Misrock Foundation (Fellowship

Reactivity of Tetrel-Functionalized Heptaphosphane Clusters toward Azides

In this work, the reactivity of tetrel-functionalized phosphorus clusters toward organoazides is probed. Clusters (Me3Si)3P7 (1) and (Me3Ge)3P7 (2) were reacted with benzyl azide, phenyl azide, and 4-bromophenyl azide, and it was found that the [RN] (R = benzyl, phenyl, and 4-bromophenyl) unit from the azide inserted into the phosphorus–tetrel bonds on the cluster, accompanied by N2 elimination. Through control of the azide stoichiometry, the mono-, bis-, and tris-inserted products could be observed, consistent with these insertions proceeding in a stepwise manner. The bonding between the amine moieties and clusters was further investigated by computational chemistry, and the findings were consistent with the phosphorus cluster having undergone a formal oxidation. These insertion reactions are a convenient means of accessing Zintl clusters functionalized with exo-nitrogen-bonded moieties, which, to the best of our knowledge, were previously unknown