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Four new and one previously reported silver 4,4'-vinylenedipyridine (Vpe) coordination polymers were tested as anion exchange materials to assess their potential for pollutant sequestration and compared to analogous silver 4,4'-bipyridine (bipy) coordination polymers. The materials were synthesized using nitrate, tetrafluoroborate, perchlorate, perrhenate, or chromate as the anion to produce cationic coordination polymers with solubilities ranging from 0.0137(7) to 0.21(5) mM. These values are much lower than silver bipy coordination polymers [0.045(3) to 5.5(5) mM] and agree with thermochemical calculations. [Ag(Vpe)+][BF4-], [Ag2(Vpe)2.52+][CrO42-]·5H2O, and [Ag(Vpe)+][ReO4-]·2H2O structures are reported. Perrhenate and chromate ions in an equimolar solution were fully adsorbed by [Ag(Vpe)+][NO3-]·3H2O [620(2) and 137.1(6) mg/g, respectively] as well as by [Ag(Vpe)+][BF4-] [661.8(3) and 190(3) mg/g, respectively] via anion exchange. DFT calculations show that torsional energetics play a significant role in the formation thermodynamics by reducing the energy cost by as much as 4.8 kJ/mol when bipy is replaced with Vpe in silver-based coordination polymers. The results obtained with the flat Vpe ligand highlight the potential role of coordination polymers in practical anion exchange.

Organometallic antimony(V) complexes were prepared as model compounds to better understand the interactions of chiral chelating diols with this metalloid. These complexes feature three aryl groups (meta-xylyl or para-tolyl) and a bidentate trans-2,3-butanediolate. The meta-xylyl and para-tolyl complexes of either enantiomerically pure 2R,3R-butanediolate or 2S,3S-butanediolate (compounds 1-4) crystallized in Sohncke space groups, as expected. In each case, though, pseudoinversion centers were present that mimic higher-symmetry space groups through global pseudosymmetry. We hypothesized that the crystallization of 1:1 mixtures of the enantiomeric complexes would produce crystals in the centrosymmetric space group approximated by the pseudosymmetry. The enantiomerically pure meta-xylyl complexes each crystallized in space group P1 (approximating P1̅), and the racemic compound did indeed crystallize in P1̅. The enantiomerically pure para-tolyl complexes each crystallized in space group P21 (approximating P21/c), but the racemic compound crystallized in P1̅. Although the enantiomerically pure and racemic compounds are not isostructural, there are similarities in their 3D structures that are analyzed.

The heavier group 15 elements As, Sb, and Bi are more restricted in their biochemistry than the nearly ubiquitous lighter congeners N and P, but organisms do encounter compounds of these elements as environmental toxins, starting materials for secondary metabolite biosynthesis, substrates for primary metabolism, or exogenously applied medicines. Under many physiological conditions, these compounds are transformed into pnictogen(III) species, the soft Lewis acidic character of which leads them to interact strongly with biologically relevant soft Lewis bases such as small-molecule thiols or cysteine residues of proteins and peptides. The archetypal complexes As(Cys)3, Sb(Cys)3, and Bi(Cys)3 have been studied in the past but a lack of detailed information about their molecular structures has hampered the analysis of protein structures featuring As(III), Sb(III), and Bi(III) bound to cysteine thiolate residues. In many cases, the formation of such protein adducts is proposed to play a key role in the mechanism of action of inorganic drugs that feature these elements. Here, we refine synthetic strategies to access As(Cys)3, Sb(Cys)3, and Bi(Cys)3, describe their crystal structures, analyze structural trends across the series and across Pn(SR)3 compounds deposited in the Cambridge Structural Database, and compare their features to the structures of proteins with these centers bound to Cys3 motifs. Significant differences were noted for many of the protein structures.

Phosphine oxides and arsine oxides are common laboratory reagents with diverse applications that stem from the chemistry exhibited by these monomeric species. Stibine oxides are, in contrast, generally dimeric or oligomeric species because of the reactivity-quenching self-association of the highly polarized stiboryl (Sb=O/Sb+-O-) group. We recently isolated Dipp3SbO (Dipp = 2,6-diisopropylphenyl), the first example of a kinetically stabilized monomeric stibine oxide, which exists as a bench-stable solid and bears an unperturbed stiboryl group. Herein, we report the isolation of Mes3SbO (Mes = mesityl), in which the less bulky substituents maintain the monomeric nature of the compound but unlock access to a wider range of reactivity at the unperturbed stiboryl group relative to Dipp3SbO. Mes3SbO was found to be a potent Lewis base in the formation of adducts with the main-group Lewis acids PbMe3Cl and SnMe3Cl. The accessible Lewis acidity at the Sb atom results in a change in the reactivity with GeMe3Cl, SiMe3Cl, and CPh3Cl. With these species, Mes3SbO formally adds the E-Cl (E = Ge, Si, C) bond across the unsaturated stiboryl group to form a 5-coordinate stiborane. The biphilicity of Mes3SbO is sufficiently potent to activate even the C-F and Si-F bonds of C(p-MeOPh)3F and SiEt3F, respectively. These results mark a significant contribution to an increasingly rich literature on the reactivity of polar, unsaturated main-group motifs. Furthermore, these results highlight the utility of a kinetic stabilization approach to access unusual bonding motifs with unquenched reactivity that can be leveraged for small-molecule activation.

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.

The elucidation of novel bonding situations at heavy p-block elements has greatly advanced recent efforts to access useful reactivity at earth-abundant main-group elements. Molecules with unsaturated bonds between heavier, electropositive elements and lighter, electronegative elements are often highly polarized and competent in small-molecule activations, but the reactivity of these molecules may be quenched by self-association of monomers to form oligomeric species where the polar, unsaturated groups are assembled in a head-to-tail fashion. In this Frontier, we discuss the synthetic strategies employed to isolate monomeric σ2,λ3-stibinidene chalcogenides (RSbCh) and monomeric σ4,λ5-stibine chalcogenides (R3SbCh). These classes of molecules each feature polarized antimony-chalcogenide bonds (Sb = Ch/Sb+-Ch-). We highlight how the synthesis and isolation of these molecules has led to the discovery of novel reactivity and has shed light on fundamental aspects of inorganic structure and bonding. Despite these advances, there are critical aspects of this chemistry that remain underdeveloped and we provide our perspective on yet-unrealized synthetic targets that may be achieved with the continued development of the strategies described herein.

Abstract: Structure elucidation plays a critical role across the landscape of medicinal chemistry, including medicinal inorganic chemistry. Herein, we discuss the importance of structure elucidation in drug development and then provide three vignettes that capture key instances of its relevance in the development of biologically active inorganic compounds. In the first, we describe the exploration of the biological activity of the trinuclear Ru compound called ruthenium red and the realization that this activity derived from a dinuclear impurity. We next explore the development of Au‐based antitubercular and antiarthritic drugs, which features a key step whereby ligands were discovered to bind to Au through S atoms. The third exposition traces the development of As‐based antiparasitic drugs, a key step of which was the realization that the reaction of arsenic acid and aniline does not produce an anilide of arsenic acid, as originally thought, but rather an amino arsonic acid. These case studies provide the motivation for an outlook in which the development of Sb‐based antiparasitic drugs is described. Although antileishmanial pentavalent antimonial drugs remain in widespread use to this day, their chemical structures remain unknown.

Carbon monoxide poisoning is one of the most common forms of poisoning in the world. Although the primary mode of treatment, oxygen therapy, is highly effective in many cases, there are instances in which it is inadequate or inappropriate. Whereas oxygen therapy relies on high levels of a low-affinity ligand (O2) to displace a high-affinity ligand (CO) from metalloproteins, an antidote strategy relies on introducing a molecule with a higher affinity for CO than native proteins (Kantidote,CO > Kprotein,CO). Based on the fundamental chemistry of CO, such an antidote is most likely required to be an inorganic compound featuring an electron-rich transition metal. A review is provided of the protein-, supramolecular complex-, and small molecule-based CO poisoning antidote platforms that are currently under investigation.

PYTA is demonstrated to rapidly and stably complex 225Ac, 177Lu, 111In, and 44Sc, a “superfecta” of complementary but chemically distinct radiometals for targeted theranostic applications.

Phosphine oxides and arsine oxides feature highly polarized pnictoryl groups (Pn+-O-/Pn = O; Pn = P, As) and react as Brønsted bases through O-centered lone pairs. We recently reported the first example of a monomeric stibine oxide, Dipp3SbO (Dipp = diisopropylphenyl), allowing periodic trends in pnictoryl bonding to be extended to antimony for the first time. Computational studies suggest that, as the pnictogen atom becomes heavier, delocalization of electron density from the O-centered lone pairs to the Pn-C σ* orbitals is attenuated, destabilizing the lone pairs and increasing the donor capacity of the pnictine oxide. Herein, we assess the Brønsted basicity of a series of monomeric pnictine oxides (Dipp3PnO; Pn = P, As, and Sb). Stoichiometric reactivity between Dipp3PnO and a series of acids demonstrates the greatly enhanced ability of Dipp3SbO to accept protons relative to the lighter congeners, consistent with theoretical isodesmic reaction enthalpies and proton affinities. 1H NMR spectrometric titrations allow for the pKaH,MeCN determination of Dipp3AsO and Dipp3SbO, revealing a 106-fold increase in Brønsted basicity from Dipp3AsO to Dipp3SbO. The increased basicity can be exploited in catalysis; Dipp3SbO exhibits dramatically increased catalytic efficiency in the Brønsted base-catalyzed transesterification between p-nitrophenyl acetate and 2,2,2-trifluoroethanol. Our results unambiguously confirm the drastic increase in Brønsted basicity from Dipp3PO < Dipp3AsO < Dipp3SbO, a direct consequence of the variation in the electronic structure of the pnictoryl bond as the pnictogen atom increases in atomic number.

The structures of the pentavalent antimonials, small-molecule Sb-containing drugs used to treat the neglected tropical disease leishmaniasis, remain unknown despite their widespread use for over half a century. These drugs are prepared by combination of an Sb(V) precursor and a sugar derivative and proposed structures frequently invoke a cyclic stiborane motif in which a vicinal diolate ligand chelates an Sb(V) center. As a step towards better understanding the structures of the pentavalent antimonial drugs, a series of cyclic organostiboranes spanning the stereochemical space afforded by a vicinal diolate motif has been synthesized and characterized. X-ray crystallography and NMR spectroscopy provide unambiguous characterization of the structures of these model compounds and of the interaction of the diolate with the Sb(V) center. Particularly notable are the systematic trends observed in the NMR spectroscopic signals as a function of the stereochemistry of the diolate. The spectroscopic signatures identified with these model compounds will provide a framework for elucidating the structures of the pentavalent antimonial drugs.

In contrast to phosphine oxides and arsine oxides, which are common and exist as stable monomeric species featuring the corresponding pnictoryl functional group (Pn=O/Pn+-O-; Pn = P, As), stibine oxides are generally polymeric, and the properties of the unperturbed stiboryl group (Sb=O/Sb+-O-) remain unexplored. We now report the isolation of the monomeric stibine oxide, Dipp3SbO (where Dipp = 2,6-diisopropylphenyl). Spectroscopic, crystallographic and computational studies provide insight into the nature of the Sb=O/Sb+-O- bond. Moreover, isolation of Dipp3SbO allows the chemistry of the stiboryl group to be explored. Here we show that Dipp3SbO can act as a Brønsted base, a hydrogen-bond acceptor and a transition-metal ligand, in addition engaging in 1,2-addition, O-for-F2 exchange and O-atom transfer. In all cases, the reactivity of Dipp3SbO differed from that of the lighter congeners Dipp3AsO and Dipp3PO.

Arsenic trioxide (ATO) is an approved therapy for the treatment of acute promyelocytic leukemia, but the extension of arsenic-based therapies to other types of malignancies, notably tumor-forming cancers, has been slow. Nanodelivery vehicles offer a means of effectively delivering ATO to tumors. Very recently, there has been a series of developments in the formulation of arsenic-based nanomedicines that are not simply loaded with ATO. Realgar nanoparticles are comprised of molecular As4S4 units. Current studies suggest that realgar nanoparticles ultimately act in a manner similar to ATO, but with greatly attenuated toxic side effects. A drastically different approach is taken with arsenene nanosheets, a 2-dimensional form of elemental As. The electronic properties of this material allow it to mediate both photothermal therapy and photodynamic therapy. The exploration of these nanomaterials is still in its infancy but is poised to allow arsenic-based therapy to make yet another significant impact on cancer treatment.

Abstract: We report the first total synthesis of an antimycobacterial natural product oxazinin A that takes advantage of a multi‐component cascade reaction of anthranilic acid and a precursor polyketide containing an aldehyde. The route utilized for the synthesis of the pseudodimeric oxazinin A validates a previously proposed biosynthetic mechanism, invoking a non‐enzymatic pathway to the complex molecule. We found a 76 : 10 : 9 : 5 ratio of oxazinin diastereomers from the synthetic cascade, which is an identical match to that found in the fermentation media from the fungus Eurotiomycetes 110162. Further investigation of the non‐enzymatic formation of oxazinin A using 1H‐15N HMBC NMR spectroscopy allowed for a plausible determination of the stepwise mechanism. The developed route is highly amenable for the synthesis of diverse sets of analogs around the oxazinin scaffold to study structure–activity relationships (SAR).

We report the first total synthesis of an antimycobacterial natural product oxazinin A that takes advantage of a multi-component cascade reaction of anthranilic acid and a precursor polyketide containing an aldehyde. The route utilized for the synthesis of the pseudodimeric oxazinin A validates a previously proposed biosynthetic mechanism, invoking a non-enzymatic pathway to the complex molecule. We found a 76 : 10 : 9 : 5 ratio of oxazinin diastereomers from the synthetic cascade, which is an identical match to that found in the fermentation media from the fungus Eurotiomycetes 110162. Further investigation of the non-enzymatic formation of oxazinin A using 1 H-15 N HMBC NMR spectroscopy allowed for a plausible determination of the stepwise mechanism. The developed route is highly amenable for the synthesis of diverse sets of analogs around the oxazinin scaffold to study structure-activity relationships (SAR).

Herein we report an investigation into the synthesis, metalation, and functionalization of bis-pocket porphyrins using the Suzuki-Miyaura cross-coupling reaction. Steric limitations to accessing bis-pocket porphyrins were overcome by using this Pd-catalyzed C-C-bond-forming strategy to introduce steric bulk after macrocyclization: 2,6-dibromo-4-trimethylsilybenzaldehyde was condensed with pyrrole, and a variety of boronic acids were coupled to the resulting porphyrin in up to 95% yield. Furthermore, we show that these porphyrins can be metalated with a variety of metals and sulfonated to create water-soluble bis-pocket porphyrins.

The rippled β-sheet is a peptidic structural motif related to but distinct from the pleated β-sheet. Both motifs were predicted in the 1950s by Pauling and Corey. The pleated β-sheet was since observed in countless proteins and peptides and is considered common textbook knowledge. Conversely, the rippled β-sheet only gained a meaningful experimental foundation in the past decade, and the first crystal structural study of rippled β-sheets was published as recently as this year. Noteworthy, the crystallized assembly stopped at the rippled β-dimer stage. It did not form the extended, periodic rippled β-sheet layer topography hypothesized by Pauling and Corey, thus calling the validity of their prediction into question. NMR work conducted since moreover shows that certain model peptides rather form pleated and not rippled β-sheets in solution. To determine whether the periodic rippled β-sheet layer configuration is viable, the field urgently needs crystal structures. Here we report on crystal structures of two racemic and one quasi-racemic aggregating peptide systems, all of which yield periodic rippled antiparallel β-sheet layers that are in excellent agreement with the predictions by Pauling and Corey. Our study establishes the rippled β-sheet layer configuration as a motif with general features and opens the road to structure-based design of unique supramolecular architectures.

Despite the notoriously poor membrane permeability of peptides, many cyclic peptide natural products show high passive membrane permeability and potently inhibit a variety of "undruggable" intracellular targets. A major impediment to the design of cyclic peptides with good permeability is the high desolvation energy associated with the peptide backbone amide NH groups. While several strategies have been proposed to mitigate this deleterious effect, only few studies have used polar side chains to sequester backbone NH groups. We investigated the ability of N,N-pyrrolidinylglutamine (Pye), whose side chain contains a powerful hydrogen-bond-accepting C═O amide group but no hydrogen-bond donors, to sequester exposed backbone NH groups in a series of cyclic hexapeptide diastereomers. Analyses revealed that specific Leu-to-Pye substitutions conferred dramatic improvements in aqueous solubility and permeability in a scaffold- and position-dependent manner. Therefore, this approach offers a complementary tool for improving membrane permeability and solubility in cyclic peptides.

We describe herein a small-molecule platform that exhibits key properties needed by an antidote for CO poisoning. The design features an iron-porphyrin complex with bulky substituents above and below the macrocyclic plane to provide a hydrophobic pocket for CO binding and to prevent the formation of inactive oxo-bridged dimers. Peripheral charged groups impart water solubility. We demonstrate that the Fe(II) complex of a porphyrin with 2,6-diphenyl-4-sulfophenyl meso substituents can bind CO, stoichiometrically sequester CO from carboxyhemoglobin, and rescue CO-poisoned red blood cells.

Na2B12I12 has many of the properties desired by an X-ray contrast agent but is lethal at the concentrations needed for medical imaging. We demonstrate here that PBS solutions with >50 mM Na2B12I12 induce hemolysis, consistent with the previously reported superchaotropic nature of the anion. The presence of

Following the seminal theoretical work on the pleated β-sheet published by Pauling and Corey in 1951, the rippled β-sheet was hypothesized by the same authors in 1953. In the pleated β-sheet the interacting β-strands have the same chirality, whereas in the rippled β-sheet the interacting β-strands are mirror-images. Unlike with the pleated β-sheet that is now common textbook knowledge, the rippled β-sheet has been much slower to evolve. Much of the experimental work on rippled sheets came from groups that study aggregating racemic peptide systems over the course of the past decade. This includes MAX1/DMAX hydrogels (Schneider), L/D-KFE8 aggregating systems (Nilsson), and racemic Amyloid β mixtures (Raskatov). Whether a racemic peptide mixture is "ripple-genic" (i.e., whether it forms a rippled sheet) or "pleat-genic" (i.e., whether it forms a pleated sheet) is likely governed by a complex interplay of thermodynamic and kinetic effects. Structural insights into rippled sheets remain limited to only a very few studies that combined sparse experimental structural constraints with molecular modeling. Crystal structures of rippled sheets are needed so we can rationally design rippled sheet architectures. Here we report a high-resolution crystal structure, in which (l,l,l)-triphenylalanine and (d,d,d)-triphenylalanine form dimeric antiparallel rippled sheets, which pack into herringbone layer structures. The arrangements of the tripeptides and their mirror-images in the individual dimers were in excellent agreement with the theoretical predictions by Pauling and Corey. A subsequent mining of the PDB identified three orphaned rippled sheets among racemic protein crystal structures.

Neutron wavelength-resolved Laue diffraction experiments permit accurate refinement of the H-atom positions and anisotropic displacement parameters of [Mes3SbOH][O3SPh]. A multipole-based charge density refinement and a topological analysis of the refined electron density were also performed. Hirshfeld atom refinement (HAR) recovers the neutron-determined H-atom parameters, and the quantum-mechanical electron density used in HAR recovers the electron density topology from the refined multipole model. These results confirm that [Mes3SbOH][O3SPh] does indeed feature a hydroxystibonium cation with a nominal Sb-O single bond and not a stibine oxide with an Sb=O/Sb+-O- bond.

Ferric complexes of triscatechol siderophores may assume one of two enantiomeric configurations at the iron site. Chirality is known to be important in the iron uptake process, however an understanding of the molecular features directing stereospecific coordination remains ambiguous. Synthesis of the full suite of (DHBL/DLysL/DSer)3 macrolactone diastereomers, which includes the siderophore cyclic trichrysobactin (CTC), enables the effects that the chirality of Lys and Ser residues exert on the configuration of the Fe(iii) complex to be defined. Computationally optimized geometries indicate that the Λ/Δ configurational preferences are set by steric interactions between the Lys sidechains and the peptide backbone. The ability of each (DHBL/DLysL/DSer)3 diastereomer to form a stable Fe(iii) complex prompted a genomic search for biosynthetic gene clusters (BGCs) encoding the synthesis of these diastereomers in microbes. The genome of the plant pathogen Dickeya chrysanthemi EC16 was sequenced and the genes responsible for the biosynthesis of CTC were identified. A related but distinct BGC was identified in the genome of the opportunistic pathogen Yersinia frederiksenii ATCC 33641; isolation of the siderophore from Y. frederiksenii ATCC 33641, named frederiksenibactin (FSB), revealed the triscatechol oligoester, linear-(DHBLLysLSer)3. Circular dichroism (CD) spectroscopy establishes that Fe(iii)-CTC and Fe(iii)-FSB are formed in opposite enantiomeric configuration, consistent with the results of the ferric complexes of the cyclic (DHBL/DLysL/DSer)3 diastereomers.

Ferric complexes of triscatechol siderophores may assume one of two enantiomeric configurations at the iron site. Chirality is known to be important in the iron uptake process, however an understanding of the molecular features directing stereospecific coordination remains ambiguous. Synthesis of the full suite of (DHBL/DLysL/DSer)3 macrolactone diastereomers, which includes the siderophore cyclic trichrysobactin (CTC), enables the effects that the chirality of Lys and Ser residues exert on the configuration of the Fe(iii) complex to be defined. Computationally optimized geometries indicate that the Λ/Δ configurational preferences are set by steric interactions between the Lys sidechains and the peptide backbone. The ability of each (DHBL/DLysL/DSer)3 diastereomer to form a stable Fe(iii) complex prompted a genomic search for biosynthetic gene clusters (BGCs) encoding the synthesis of these diastereomers in microbes. The genome of the plant pathogen Dickeya chrysanthemi EC16 was sequenced and the genes responsible for the biosynthesis of CTC were identified. A related but distinct BGC was identified in the genome of the opportunistic pathogen Yersinia frederiksenii ATCC 33641; isolation of the siderophore from Y. frederiksenii ATCC 33641, named frederiksenibactin (FSB), revealed the triscatechol oligoester, linear-(DHBLLysLSer)3. Circular dichroism (CD) spectroscopy establishes that Fe(iii)-CTC and Fe(iii)-FSB are formed in opposite enantiomeric configuration, consistent with the results of the ferric complexes of the cyclic (DHBL/DLysL/DSer)3 diastereomers.

Attempts to investigate the properties and reactivity of the stiboryl moiety (R3Sb+-O- or R3Sb[double bond, length as m-dash]O), as in monomeric stibine oxides free of interaction with Lewis acids/bases, led us to conclude that this functional group remains undiscovered. X-ray crystallographic, computational, and spectroscopic data indicate that previously proposed H-bonded stibine oxide adducts Mes3SbOHO3SR are in fact hydroxystibonium salts [Mes3SbOH][RSO3].

Attempts to investigate the properties and reactivity of the stiboryl moiety (R3Sb+-O- or R3Sb[double bond, length as m-dash]O), as in monomeric stibine oxides free of interaction with Lewis acids/bases, led us to conclude that this functional group remains undiscovered. X-ray crystallographic, computational, and spectroscopic data indicate that previously proposed H-bonded stibine oxide adducts Mes3SbOHO3SR are in fact hydroxystibonium salts [Mes3SbOH][RSO3].

The design and synthesis of narrow-spectrum antibiotics that target a specific bacterial strain, species, or group of species is a promising strategy for treating bacterial infections when the causative agent is known. In this work, we report the synthesis and evaluation of four new siderophore-β-lactam conjugates where the broad-spectrum β-lactam antibiotics cephalexin (Lex) and meropenem (Mem) are covalently attached to either enterobactin (Ent) or diglucosylated Ent (DGE) via a stable polyethylene glycol (PEG3) linker. These siderophore-β-lactam conjugates showed enhanced minimum inhibitory concentrations against Escherichia coli compared to the parent antibiotics. Uptake studies with uropathogenic E. coli CFT073 demonstrated that the DGE-β-lactams target the pathogen-associated catecholate siderophore receptor IroN. A comparative analysis of siderophore-β-lactams harboring ampicillin (Amp), Lex and Mem indicated that the DGE-Mem conjugate is advantageous because it targets IroN and exhibits low minimum inhibitory concentrations, fast time-kill kinetics, and enhanced stability to serine β-lactamases. Phase-contrast and fluorescence imaging of E. coli treated with the siderophore-β-lactam conjugates revealed cellular morphologies consistent with the inhibition of penicillin-binding proteins PBP3 (Ent/DGE-Amp/Lex) and PBP2 (Ent/DGE-Mem). Overall, this work illuminates the uptake and cell-killing activity of Ent- and DGE-β-lactam conjugates against E. coli and supports that native siderophore scaffolds provide the opportunity for narrowing the activity spectrum of antibiotics in clinical use and targeting pathogenicity.

The design and synthesis of narrow-spectrum antibiotics that target a specific bacterial strain, species, or group of species is a promising strategy for treating bacterial infections when the causative agent is known. In this work, we report the synthesis and evaluation of four new siderophore-β-lactam conjugates where the broad-spectrum β-lactam antibiotics cephalexin (Lex) and meropenem (Mem) are covalently attached to either enterobactin (Ent) or diglucosylated Ent (DGE) via a stable polyethylene glycol (PEG3) linker. These siderophore-β-lactam conjugates showed enhanced minimum inhibitory concentrations against Escherichia coli compared to the parent antibiotics. Uptake studies with uropathogenic E. coli CFT073 demonstrated that the DGE-β-lactams target the pathogen-associated catecholate siderophore receptor IroN. A comparative analysis of siderophore-β-lactams harboring ampicillin (Amp), Lex and Mem indicated that the DGE-Mem conjugate is advantageous because it targets IroN and exhibits low minimum inhibitory concentrations, fast time-kill kinetics, and enhanced stability to serine β-lactamases. Phase-contrast and fluorescence imaging of E. coli treated with the siderophore-β-lactam conjugates revealed cellular morphologies consistent with the inhibition of penicillin-binding proteins PBP3 (Ent/DGE-Amp/Lex) and PBP2 (Ent/DGE-Mem). Overall, this work illuminates the uptake and cell-killing activity of Ent- and DGE-β-lactam conjugates against E. coli and supports that native siderophore scaffolds provide the opportunity for narrowing the activity spectrum of antibiotics in clinical use and targeting pathogenicity.

The use of a bis(diphenyl)phosphine functionalized β-diketiminato ligand, [HC{(CH3 )C}2 {(ortho-[P(C6 H5 )2 ]2 C6 H4 )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.

The use of a bis(diphenyl)phosphine functionalized β-diketiminato ligand, [HC{(CH3 )C}2 {(ortho-[P(C6 H5 )2 ]2 C6 H4 )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.

Enterobactin is a secondary metabolite produced by Enterobacteriaceae for acquiring iron, an essential metal nutrient. The biosynthesis and utilization of enterobactin permits many Gram-negative bacteria to thrive in environments where low soluble iron concentrations would otherwise preclude survival. Despite extensive work carried out on this celebrated molecule since its discovery over 40 years ago, the ferric enterobactin complex has eluded crystallographic structural characterization. We report the successful growth of single crystals containing ferric enterobactin using racemic crystallization, a method that involves cocrystallization of a chiral molecule with its mirror image. The structures of ferric enterobactin and ferric enantioenterobactin obtained in this work provide a definitive assignment of the stereochemistry at the metal center and reveal secondary coordination sphere interactions. The structures were employed in computational investigations of the interactions of these complexes with two enterobactin-binding proteins, which illuminate the influence of metal-centered chirality on these interactions. This work highlights the utility of small-molecule racemic crystallography for obtaining elusive structures of coordination complexes.

A microfluidic strategy has been used for the time- and labour-efficient evaluation of the relative efficiency and thermodynamic parameters of CO2 binding by three Lewis acid/base combinations, where efficiency is based on the amount of CO2 taken up per binding unit in solution. Neither tBu3P nor B(C6F5)3 were independently effective at CO2 capture, and the combination of the imidazolin-2-ylidenamino-substituted phosphine (NIiPr)3P and B(C6F5)3 was equally ineffective. Nonetheless, an archetypal frustrated Lewis pair (FLP) comprised of tBu3P and B(C6F5)3 was shown to bind CO2 more efficiently than either the FLP derived from tetramethylpiperidine (TMP) and B(C6F5)3 or the highly basic phosphine (NIiPr)3P. Moreover, the proposed microfluidic platform was used to elucidate the thermodynamic parameters for these reactions.

A microfluidic strategy has been used for the time- and labour-efficient evaluation of the relative efficiency and thermodynamic parameters of CO2 binding by three Lewis acid/base combinations, where efficiency is based on the amount of CO2 taken up per binding unit in solution. Neither tBu3P nor B(C6F5)3 were independently effective at CO2 capture, and the combination of the imidazolin-2-ylidenamino-substituted phosphine (NIiPr)3P and B(C6F5)3 was equally ineffective. Nonetheless, an archetypal frustrated Lewis pair (FLP) comprised of tBu3P and B(C6F5)3 was shown to bind CO2 more efficiently than either the FLP derived from tetramethylpiperidine (TMP) and B(C6F5)3 or the highly basic phosphine (NIiPr)3P. Moreover, the proposed microfluidic platform was used to elucidate the thermodynamic parameters for these reactions.

The monofunctional platinum anticancer agent phenanthriplatin generates covalent adducts with the purine bases guanine and adenine. Preferential nucleotide binding was investigated by using a polymerase stop assay and linear DNA amplification with a 163-base pair DNA double helix. Similarly to cisplatin, phenanthriplatin forms the majority of adducts at guanosine residues, but significant differences in both the number and position of platination sites emerge when comparing results for the two complexes. Notably, the monofunctional complex generates a greater number of polymerase-halting lesions at adenosine residues than does cisplatin. Studies with 9-methyladenine reveal that, under abiological conditions, phenanthriplatin binds to the N(1) or N(7) position of 9-methyladenine in approximately equimolar amounts. By contrast, comparable reactions with 9-methylguanine afforded only the N(7) -bound species. Both of the 9-methyladenine linkage isomers (N(1) and N(7) ) exist as two diastereomeric species, arising from hindered rotation of the aromatic ligands about their respective platinum-nitrogen bonds. Eyring analysis of rate constants extracted from variable-temperature NMR spectroscopic data revealed that the activation energies for ligand rotation in the N(1) -bound platinum complex and the N(7) -linkage isomers are comparable. Finally, a kinetic analysis indicated that phenanthriplatin reacts more rapidly, by a factor of eight, with 9-methylguanine than with 9-methyladenine, suggesting that the distribution of lesions formed on double-stranded DNA is kinetically controlled. In addition, implications for the potent anticancer activity of phenanthriplatin are discussed herein.

The platinum drugs, cisplatin, carboplatin, and oxaliplatin, prevail in the treatment of cancer, but new platinum agents have been very slow to enter the clinic. Recently, however, there has been a surge of activity, based on a great deal of mechanistic information, aimed at developing nonclassical platinum complexes that operate via mechanisms of action distinct from those of the approved drugs. The use of nanodelivery devices has also grown, and many different strategies have been explored to incorporate platinum warheads into nanomedicine constructs. In this Review, we discuss these efforts to create the next generation of platinum anticancer drugs. The introduction provides the reader with a brief overview of the use, development, and mechanism of action of the approved platinum drugs to provide the context in which more recent research has flourished. We then describe approaches that explore nonclassical platinum(II) complexes with trans geometry or with a monofunctional coordination mode, polynuclear platinum(II) compounds, platinum(IV) prodrugs, dual-threat agents, and photoactivatable platinum(IV) complexes. Nanoparticles designed to deliver platinum(IV) complexes will also be discussed, including carbon nanotubes, carbon nanoparticles, gold nanoparticles, quantum dots, upconversion nanoparticles, and polymeric micelles. Additional nanoformulations, including supramolecular self-assembled structures, proteins, peptides, metal-organic frameworks, and coordination polymers, will then be described. Finally, the significant clinical progress made by nanoparticle formulations of platinum(II) agents will be reviewed. We anticipate that such a synthesis of disparate research efforts will not only help to generate new drug development ideas and strategies, but also will reflect our optimism that the next generation of approved platinum cancer drugs is about to arrive.

Three rationally designed glucose-platinum conjugates (Glc-Pts) were synthesized and their biological activities evaluated. The Glc-Pts, 1-3, exhibit high levels of cytotoxicity toward a panel of cancer cells. The subcellular target and cellular uptake mechanism of the Glc-Pts were elucidated. For uptake into cells, Glc-Pt 1 exploits both glucose and organic cation transporters, both widely overexpressed in cancer. Compound 1 preferentially accumulates in and annihilates cancer, compared to normal epithelial, cells in vitro.

Rhenium(V) oxo complexes of general formula [ReO(OMe)(N^N)Cl2], where N^N = 4,7-diphenyl-1,10-phenanthroline, 1, or 3,4,7,8-tetramethyl-1,10-phenanthroline, 2, effectively kill cancer cells by triggering necroptosis, a non-apoptotic form of cell death. Both complexes evoke necrosome (RIP1-RIP3)-dependent intracellular reactive oxygen species (ROS) production and propidium iodide uptake. The complexes also induce mitochondrial membrane potential depletion, a possible downstream effect of ROS production. Apparently, 1 and 2 are the first rhenium complexes to evoke cellular events consistent with programmed necrosis in cancer cells. Furthermore, 1 and 2 display low acute toxicity in C57BL/6 mice and reasonable stability in fresh human blood.

This report presents a novel strategy that facilitates delivery of multiple, specific payloads of Pt(IV) prodrugs using a well-defined supramolecular system. This delivery system comprises a hexanuclear Pt(II) cage that can host four Pt(IV) prodrug guest molecules. Relying on host-guest interactions between adamantyl units tethered to the Pt(IV) molecules and the cage, four prodrugs could be encapsulated within one cage. This host-guest complex, exhibiting a diameter of about 3 nm, has been characterized by detailed NMR spectroscopic measurements. Owing to the high positive charge, this nanostructure exhibits high cellular uptake. Upon entering cells and reacting with biological reductants such as ascorbic acid, the host-guest complex releases cisplatin, which leads to cell cycle arrest and apoptosis. The fully assembled complex displays cytotoxicity comparable to that of cisplatin against a panel of human cancer cells lines, whereas the cage or the Pt(IV) guest alone exhibit lower cytotoxicity. These findings indicate the potential of utilising well-defined supramolecular constructs for the delivery of prodrug molecules.

This report presents a novel strategy that facilitates delivery of multiple, specific payloads of Pt(IV) prodrugs using a well-defined supramolecular system. This delivery system comprises a hexanuclear Pt(II) cage that can host four Pt(IV) prodrug guest molecules. Relying on host-guest interactions between adamantyl units tethered to the Pt(IV) molecules and the cage, four prodrugs could be encapsulated within one cage. This host-guest complex, exhibiting a diameter of about 3 nm, has been characterized by detailed NMR spectroscopic measurements. Owing to the high positive charge, this nanostructure exhibits high cellular uptake. Upon entering cells and reacting with biological reductants such as ascorbic acid, the host-guest complex releases cisplatin, which leads to cell cycle arrest and apoptosis. The fully assembled complex displays cytotoxicity comparable to that of cisplatin against a panel of human cancer cells lines, whereas the cage or the Pt(IV) guest alone exhibit lower cytotoxicity. These findings indicate the potential of utilising well-defined supramolecular constructs for the delivery of prodrug molecules.

Mixed amine/ammine motifs are important features in newer generation platinum anticancer agents, including the Pt(IV) prodrug satraplatin. One synthetic route that can be used to access platinum molecules with such structures exploits the trans effect during NH3-mediated cleavage of iodo-bridged platinum(II) dimers of the form [Pt(Am)I(μ-I)]2, where Am is an amine. A clear picture of the nature of these dimers that is consistent with the reactivity they exhibit has remained elusive. Moreover, technical aspects of this chemistry have impeded its more widespread use. We present here an improved strategy that permits isolation and use of [Pt(Am)I(μ-I)]2, where Am is cyclohexylamine, within minutes as opposed to weeks, as previously reported. A detailed spectroscopic, crystallographic, and chromatographic investigation of this intermediate in the synthesis of satraplatin is also presented with a discussion of the ability of both cis and trans isomers of the dimer to produce exclusively cis-[Pt(NH2C6H11)(NH3)I2] upon treatment with NH3.

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.

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.

Albumin is the most abundant protein in human serum and drugs that are administered intravenously inevitably interact with it. We present here a series of platinum(IV) prodrugs designed specifically to enhance interaction with human serum albumin (HSA) for drug delivery. This goal is achieved by asymmetrically functionalizing the axial ligands of the prodrug so as to mimic the overall features of a fatty acid. Systematic variation of the length of the aliphatic tail tunes the cellular uptake and, consequently, the cytotoxicity of cis,cis,trans-[Pt(NH3)2Cl2(O2CCH2CH2COOH)(OCONHR)], 4, where R is a linear alkyl group. Investigation of an analogue bearing a fluorophore conjugated to the succinate ligand confirmed that these compounds are reduced by biological reductants with loss of the axial ligands. Intracellular release of cisplatin from 4 was further confirmed by observing the characteristic effects of cisplatin on the cell cycle and morphology following treatment with the prodrug. The most potent member of series 4, for which R is a hexadecyl chain, interacts with HSA in a 1:1 stoichiometry to form the platinum-protein complex 7. The interaction is non-covalent and extraction with octanol completely removes the prodrug from an aqueous solution of HSA. Construct 7 is robust and can be isolated following fast protein liquid chromatography. The nature of the tight interaction was investigated computationally, and these studies suggest that the prodrug is buried below the surface of the protein. Consequently, complexation to HSA is able to reduce the rate of reduction of the prodrug by ascorbate. The lead compound from series 4 also exhibited significant stability in whole human blood, attributed to its interaction with HSA. This favorable redox profile, in conjunction with the established nonimmunogenicity, biocompatibility, and enhanced tumor accumulation of HSA, produces a system that holds significant therapeutic potential.

Albumin is the most abundant protein in human serum and drugs that are administered intravenously inevitably interact with it. We present here a series of platinum(IV) prodrugs designed specifically to enhance interaction with human serum albumin (HSA) for drug delivery. This goal is achieved by asymmetrically functionalizing the axial ligands of the prodrug so as to mimic the overall features of a fatty acid. Systematic variation of the length of the aliphatic tail tunes the cellular uptake and, consequently, the cytotoxicity of cis,cis,trans-[Pt(NH3)2Cl2(O2CCH2CH2COOH)(OCONHR)], 4, where R is a linear alkyl group. Investigation of an analogue bearing a fluorophore conjugated to the succinate ligand confirmed that these compounds are reduced by biological reductants with loss of the axial ligands. Intracellular release of cisplatin from 4 was further confirmed by observing the characteristic effects of cisplatin on the cell cycle and morphology following treatment with the prodrug. The most potent member of series 4, for which R is a hexadecyl chain, interacts with HSA in a 1:1 stoichiometry to form the platinum-protein complex 7. The interaction is non-covalent and extraction with octanol completely removes the prodrug from an aqueous solution of HSA. Construct 7 is robust and can be isolated following fast protein liquid chromatography. The nature of the tight interaction was investigated computationally, and these studies suggest that the prodrug is buried below the surface of the protein. Consequently, complexation to HSA is able to reduce the rate of reduction of the prodrug by ascorbate. The lead compound from series 4 also exhibited significant stability in whole human blood, attributed to its interaction with HSA. This favorable redox profile, in conjunction with the established nonimmunogenicity, biocompatibility, and enhanced tumor accumulation of HSA, produces a system that holds significant therapeutic potential.

The Pt(IV) complex c,c,t-[Pt(NH3)2Cl2(OH)2] is an important intermediate in the synthesis of Pt(IV) anticancer prodrugs and has been investigated as an anticancer agent in its own right. An analysis of the vibrational spectroscopy of this molecule was previously reported (Faggiani et al., Can. J. Chem. 60:529, 1982), in which crystallographic determination of the structure of the complex permitted a site group approach. The space group, however, was incorrectly assigned. In the present study we have redetermined at high resolution crystal structures of c,c,t-[Pt(NH3)2Cl2(OH)2] and c,c,t-[Pt(NH3)2Cl2(OH)2]·H2O2, which makes possible discussion of the effect of hydrogen bonding on the N-H and O-H vibrational bands. The correct crystallographic site symmetry of the platinum complex in the c,c,t-[Pt(NH3)2Cl2(OH)2] structure is used to conduct a new vibrational analysis using both group-theoretical and modern density functional theory methods. This analysis reveals the nature and symmetry of the "missing band" described in the original publication and suggests a possible explanation for its disappearance.

The first near-infrared fluorescent turn-on sensor for the detection of nitroxyl (HNO), the one-electron reduced form of nitric oxide (NO), is reported. The new copper-based probe, CuDHX1, contains a dihydroxanthene (DHX) fluorophore and a cyclam derivative as a Cu(II) binding site. Upon reaction with HNO, CuDHX1 displays a five-fold fluorescence turn-on in cuvettes and is selective for HNO over thiols and reactive nitrogen and oxygen species. CuDHX1 can detect exogenously applied HNO in live mammalian cells and in conjunction with the zinc-specific, green-fluorescent sensor ZP1 can perform multicolor/multianalyte microscopic imaging. These studies reveal that HNO treatment elicits an increase in the concentration of intracellular mobile zinc.