Bioinspired ligand designs for cobalt, iron and manganese complexes : understanding mono-iron hydrogenase (Hmd)

Mono-iron hydrogenase is one of three types of hydrogenases, catalyzing reversible hydride transfer to the substrate (methenyl-H₄MPT⁺) by heterolytically cleaving molecular hydrogen into a proton and a hydride. The key features of the enzyme’s active site include a pyridone moiety, an acyl unit and facial ligation of C [superscript acyl] N [superscript pyridone] S [superscript Cys] donors. Each feature was independently incorporated into a selected ligand system (Schiff-base N4, pincer and thianthrene scaffold, respectively), in efforts to i) develop possible bioinspired catalysts for H₂ activation using earth abundant metals (iron, cobalt, manganese) and ii) make synthetic models of the enzyme active site for deeper understanding of the architecture of the active site and catalytic mechanism. Synthetic routes for making pyridone-based Schiff-base N4 and NNS type ligands were explored: although not isolated, the ligands were spectroscopically detected. On the other hand, the simpler version—pyridine-based Schiff-base N4 ligands—afforded dinuclear cobalt complexes upon metalations with cobalt(II) precursors. Depending on the length of the diamine-linker as well as the substituents on the pyridine rings, either spontaneous O₂ activation or B–F activation was observed, yielding μ-peroxo dicobalt(III) complexes or μ-fluoride bridged dicobalt(II) complexes, respectively. In particular, two μ-fluoride bridged dicobalt complexes showed antiferromagnetic coupling between the two cobalt(II) centers. From the pincer ligands featuring the unique acyl moiety within C [superscript acyl] N [superscript pyridine] S [superscript thioehter] and C [superscript acyl] N [superscript pyridine] P [superscript Ph2] donor set, the (expected) meridional and an (unexpected) facial iron-acyl complexes were isolated, respectively. Upon deprotonation (pyridine→pyridinate de-aromatization), both complexes showed reactivity towards H₂ activation; no evidence for hydride-transfer was observed. For the facial ligation, thianthrene-scaffolded manganese system was examined as a more flexible version of the anthracene-scaffolded systems. Preliminary results of the kinetic studies support the correlation between the flexibility of the scaffold and the reactivity of the metal complex, without greatly altering the electronic environment of the metal center.Chemistr

Testing Linearity Using Power Transforms of Regressors

We develop a method of testing linearity using power transforms of regressors, allowing for stationary processes and time trends. The linear model is a simplifying hypothesis that derives from the power transform model in three different ways, each producing its own identification problem. We call this modeling difficulty the trifold identification problem and show that it may be overcome using a test based on the quasi-likelihood ratio (QLR) statistic. More specifically, the QLR statistic may be approximated under each identification problem and the separate null approximations may be combined to produce a composite approximation that embodies the linear model hypothesis. The limit theory for the QLR test statistic depends on a Gaussian stochastic process. In the important special case of a linear time trend regressor and martingale difference errors asymptotic critical values of the test are provided. The paper also considers generalizations of the Box-Cox transformation, which are associated with the QLR test statistic

2009 H1N1 influenza virus infection and necrotizing pneumonia treated with extracorporeal membrane oxygenation

A 3-year-old girl with acute respiratory distress syndrome due to a H1N1 2009 influenza virus infection was complicated by necrotizing pneumonia was successfully treated with extracorporeal membrane oxygenation (ECMO). This is the first reported case in which a pediatric patient was rescued with ECMO during the H1N1 influenza epidemic in Korea in 2009

Substituent effects of N4 Schiff base ligands on the formation of fluoride-bridged dicobalt(<scp>ii</scp>) complexes <i>via</i> B–F abstraction: structures and magnetism

We report the synthesis and magnetic studies on two fluoride bridged cobalt(ii) dimers derived from propyl-bridged N4 Schiff base ligands via B–F activation.</p

CNS and CNP Iron(II) Mono-Iron Hydrogenase (Hmd) Mimics: Role of Deprotonated Methylene(acyl) and the <i>trans</i>-Acyl Site in H₂ Heterolysis

We report syntheses and H2 activation involving model complexes of mono-iron hydrogenase (Hmd) derived from acyl-containing pincer ligand precursors bearing thioether (CNSPre) or phosphine (CNPPre) donor sets. Both complexes feature pseudo-octahedral iron­(II) dicarbonyl units. While the CNS pincer adopts the expected mer-CNS (pincer) geometry, the CNP ligand unexpectedly adopts the fac-CNP coordination geometry. Both complexes exhibit surprisingly acidic methylene C–H bond (reversibly de/protonated by a bulky phenolate), which affords a putative dearomatized pyridinate-bound intermediate. Such base treatment of Fe-CNS also results in deligation of the thioether sulfur donor, generating an open coordination site trans from the acyl unit. In contrast, Fe-CNP maintains a CO ligand trans from the acyl site both in the parent and dearomatized complexes (the −PPh2 donor is cis to acyl). The dearomatized mer-Fe-CNS was competent for H2 activation (5 atm D2(g) plus phenolate as base), which is attributed to both the basic site on the ligand framework and the open coordination site trans to the acyl donor. In contrast, the dearomatized fac-Fe-CNP was not competent for H2 activation, which is ascribed to the blocked coordination site trans from acyl (occupied by CO ligand). These results highlight the importance of both (i) the open coordination site trans to the organometallic acyl donor and (ii) a pendant base in the enzyme active site

Exploring the compatibility of phosphopantetheinyl transferases with acyl carrier proteins spanning type II polyketide synthase sequence space

This paper is co-authored with 48 Haverford students from the Classes of 2023, 2024, and 2025

A TetR family regulator of an RND efflux system that directs artemisinin resistance in Vibrio cholerae

ABSTRACTArtemisinin (ARS) displayed bactericidal activity against Vibrio cholerae. To assess the mechanistic details of its antibacterial action, we have isolated V. cholerae mutants with enhanced ARS resistance and identified a gene (VCA0767) whose loss-of-function resulted in the ARS resistance phenotypes. This gene (atrR) encodes a TetR family transcriptional regulator, and its deletion mutant displayed the reduction in ARS-induced ROS formation and DNA damage. Transcriptomic analysis revealed that the genes encoding a resistance-nodulation-cell division (RND) efflux pump operon (vexRAB) and the outer membrane component (tolC) were highly upregulated in the artR mutant, suggesting that AtrR might act as a negative regulator of this operon and tolC. Gene deletion of vexR, vexB, or tolC abrogated the ARS resistance of the atrR mutant, and more importantly, the ectopic expression of VexAB-TolC was sufficient for the ARS resistance, indicating that the increased expression of the VexAB-TolC efflux system is necessary and sufficient for the ARS resistance of the atrR mutant. The cytoplasmic accumulation of ARS was compromised in the vexBtolC mutant, suggesting that the VexAB-TolC might be the primary efflux system exporting ARS to reduce its toxicity inside of the bacterial cells. The atrR mutant displayed resistance to erythromycin as well in a VexR-dependent manner. This result suggests that AtrR may act as a global regulator responsible for preventing intracellular accumulation of toxic chemicals by enhancing the RND efflux system.IMPORTANCEDrug efflux protein complexes or efflux pumps are considered as the major determinants of multiple antimicrobial resistance by exporting a wide range of structurally diverse antibiotics in bacterial pathogens. Despite the clinical significance of the increased expression of the efflux pumps, their substrate specificity and regulation mechanisms are poorly understood. Here, we demonstrated that VexAB-TolC, a resistance-nodulation-cell division (RND) efflux pump of V. cholerae, is responsible for the resistance to artemisinin (ARS), an antimalarial drug with bactericidal activity. Furthermore, we newly identified AtrR, a TetR family repressor, as a global regulator for VexRAB and the common outer membrane channel, TolC, where VexR functions as the pathway-specific regulator of the vexAB operon. Our findings will help improve our insight into a broad range of substrate specificity of the VexAB-TolC system and highlight the complex regulatory networks of the multiple RND efflux systems during V. cholerae pathogenesis

“Criss-Crossed” Dinucleating Behavior of an N4 Schiff Base Ligand: Formation of a μ‑OH,μ‑O₂ Dicobalt(III) Core via O₂ Activation

We report the synthesis and structural characterization of a dicobalt­(III) complex with a μ-OH,μ-O₂ core, namely μ-OH,μ-O₂-[Co­(enN4)]₂(X)₃ [<b>1­(ClO</b>_<b>4</b><b>)</b>_<b>3</b> and <b>1­(BF</b>_<b>4</b><b>)</b>_<b>3</b>]. The dinuclear core is cross-linked by two N4 Schiff base ligands that span each cobalt center. The formally Co^III–Co^III dimer is formed spontaneously upon exposure of the mononuclear Co­(II) complex to air and exhibits a ν­(O–O) value at 882 cm^–1 that shifts to 833 cm^–1 upon substitution with ¹⁸O₂. The CV of <b>1­(BF</b>_<b>4</b><b>)</b>_<b>3</b> exhibits a reversible {Co^III–Co^III}↔{Co^III–Co^IV} redox process, and we have investigated the oxidized {Co^III–Co^IV} species by EPR spectroscopy (<i>g</i> = 2.02, 2.06; <i>S</i> = 1/2 signal) and DFT calculations