Masking the Bioactivity of Hydroxamic Acids by Coordination to Cobalt: Towards Bioreductive Anticancer Agents.

The clinical use of many potent anticancer agents is limited by their non-selective toxicity to healthy tissue. One of these examples is vorinostat (SAHA), a pan histone deacetylase inhibitor, which shows high cytotoxicity with limited discrimination for cancerous over healthy cells. In an attempt to improve tumor selectivity, we exploited the properties of cobalt(III) as a redox-active metal center through stabilization with cyclen and cyclam tetraazamacrocycles, masking the anticancer activity of SAHA and other hydroxamic acid derivatives to allow for the complex to reach the hypoxic microenvironment of the tumor. Biological assays demonstrated the desired low in vitro anticancer activity of the complexes, suggesting effective masking of the activity of SAHA. Once in the tumor, the bioactive moiety may be released through the reduction of the CoIII center. Investigations revealed high long-term stability of the complexes, with cyclic voltammetry and chemical reduction experiments supporting the design hypothesis of SAHA release through the reduction of the CoIII prodrug. The results highlight the potential for further developing this complex class as novel anticancer agents by masking the high cytotoxicity of a given drug, however, the cellular uptake needs to be improved.

Support studies toward the hicksoane alkaloids reveal cascade reactions of a (tryptophanamido)methylglycinate.

Herein we report unanticipated results that emerged from a synthetic study targeting the unique triazocane present in the hicksoane alkaloids. An initial strategy focused on the cyclisation-ring expansion of a 3-(tryptophyl)imidazolidin-4-one failed due to the high reactivity of the imide unit; passing a methanolic solution of this compound through a weakly basic ion exchange resin led to methanolysis to form a (tryptophanamido)methylglycinate. Attempted lactamisation of this (tryptophanamido)methylglycinate led to the formation of a (tryptophyl)imidazolidin-4-one, a rare imidazopyrido[3,4-b]indolone and a ß-carboline. Control reactions informed a mechanistic rationale for these cascade processes.

An Iron Macrocyclic Complex Containing Four "Hybrid" Pyridinium Amidate/Amidate N-Donors as a Catalyst for Oxidations with Hydrogen Peroxide.

The macrocyclic proligand [H4 L][OTf]2 , which contains four carboxamide functions and two conjugated pyridinium groups, is easily deprotonated by the weak base sodium acetate to give the corresponding neutral proligand [H2 L]. Metallation of [H2 L] with iron(II) chloride proceeds rapidly to form the macrocyclic complex, [FeIII Cl(L)]. This is an effective catalyst for the oxidation of the organic dye orange II by hydrogen peroxide in aqueous solution, and the kinetic parameters for this reaction have been determined. In striking contrast to an analogous iron-TAML complex that contains two phenyl groups in place of the two pyridinium groups, [FeIII Cl(L)] is a very active oxidation catalyst at pH 7 and is also highly stable towards acid-promoted demetallation at pH 5 or above. The results show that the two pyridinium groups bring greatly enhanced catalytic properties to [FeIII Cl(L)].

Hysteretic Responses of Skyrmion Lattices to Electric Fields in Magnetoelectric Cu2OSeO3.

Electric field control of topologically nontrivial magnetic textures, such as skyrmions, provides a paradigm shift for future spintronics beyond the current silicon-based technology. While significant progress has been made by X-ray and neutron scattering studies, direct observation of such nanoscale spin structures and their dynamics driven by external electric fields remains a challenge in understanding the underlying mechanisms and harness functionalities. Here, using Lorentz transmission electron microscopy combined with in situ electric and magnetic fields at liquid helium temperatures, we report the crystallographic orientation-dependent skyrmion responses to electric fields in thin slabs of magnetoelectric Cu2OSeO3. We show that electric fields not only stabilize the hexagonally packed skyrmion lattices in the entire sample in a hysteretic manner but also induce the rotation of their reciprocal vector discretely by 30°. The nonvolatile and energy-efficient skyrmion lattice control by electric fields demonstrated in this work provides an important foundation for designing skyrmion-based qubits and memory devices.

Dissolution Mechanism of Eutectic and Hypereutectic Mg-Sn Alloy Anodes for Magnesium Rechargeable Batteries.

Magnesium rechargeable batteries (MRBs) are presently attracting much attention due to their low cost, high safety, and high theoretical volumetric capacity. Traditionally, pure magnesium metal has been used as an anode for MRBs, but its poor cycle performance, modest compatibility with conventional electrolytes, and sluggish kinetics limit the further development of MRBs. In this work, eutectic and hypereutectic Mg-Sn alloys were designed and studied as anodes for MRBs. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) results confirmed that these alloys contained unique microstructures consisting of α-Mg, Mg2Sn, and eutectic phases. The dissolution processes of the Mg-Sn alloys were studied in an all-phenyl-complex (APC) electrolyte. A multiple-step electrochemical dissolution process and a special adsorption interface layer were established for the Mg-Sn alloy anodes with an eutectic phase. Hypereutectic alloys with mixed phases showed better battery performance than the eutectic alloy owing to their superior mechanical properties. In addition, the morphology and Mg dissolution mechanism of the Mg-Sn alloys during the 1st dissolution process were characterized and discussed.

Anticancer Ru and Os complexes of N-(4-chlorophenyl)pyridine-2-carbothioamide: Substitution of the labile chlorido ligand with phosphines.

Half-sandwich MII(cym)Cl (cym = Î·6-p-cymene; M = Ru, Os) complexes of pyridinecarbothioamide (PCA) ligands have demonstrated potential as orally active anticancer agents. In order to investigate the impact of the substitution of the labile chlorido ligand with phosphorous donor ligands on the antiproliferative properties, the triphenylphosphine (PPh3) and 1,3,5-triaza-7-phophaadamantane (pta) analogues were prepared and characterized by spectroscopic techniques and the molecular structures of several complexes were determined by X-diffraction analysis. Interestingly, the molecular structures contained the PCA ligand deprotonated, presumably driven by the reduction in overall charge of the complex. Density Functional Theory (DFT) calculations suggested minor energy differences between the protonated and deprotonated forms. The aqueous stability and the reactivity with the amino acids l-histidine and l-cysteine were investigated by 1H NMR spectroscopy of representative examples. The most potent anticancer agents featured Ru or Os centers and a PPh3 ligand and showed IC50 values in the submicromolar range against four cancer cell lines. This suggests that the antiproliferative activity was mainly dependent on the lipophilic properties of the phosphine ligand with PPh3 having a significantly higher clog P value than pta.

Ferrocene-Derived Palladium(II)-Based Metallosupramolecular Structures: Synthesis, Guest Interaction, and Stimulus-Responsiveness Studies.

Using ferrocene-based ligand systems, a series of heterobimetallic architectures of the general formula [PdmLn]x+ were designed with the aim of installing an opening and closing mechanism that would allow the release and binding of guest molecules. Palladium complex formation was achieved through coordination to pyridyl groups, and using 2-, 3-, and 4-pyridyl derivatives provided access to defined PdL, PdL2, and Pd2L4 structures, respectively. The supramolecular complexes were characterized using nuclear magnetic resonance (NMR) and infrared spectroscopy, mass spectrometry, and elemental analysis, and for some examples density functional theory calculations and single-crystal X-ray diffraction analysis. 1H NMR spectroscopy was used to investigate disassembly and reassembly of the metallosupramolecular structures. The former was induced by cleavage of the relatively labile Pd-Npyridyl bonds with the introduction of the competing ligands N,N'-dimethylaminopyridine (DMAP) and Cl- (using tetrabutylammonium chloride) to yield [Pd(DMAP)4]2+ and [PdCl4]2-, respectively. The process was found to be reversible for several of the heterodimetallic compounds, with the addition of H+ or Ag+ triggering complex reassembly. Guest binding studies with several architectures revealed interactions with the anionic guests p-toluenesulfonate and octyl sulfate, but not with neutral molecules. Furthermore, the release of guests was reversibly induced with Cl- ions as a stimulus.

Triazolyl- vs Pyridyl-Functionalized N-Heterocyclic Carbene Complexes: Impact of the Pendant N-Donor Ligand on Intramolecular C-C Bond Formation.

Organometallic Rh(Cp*) (Cp* = η5-pentamethylcyclopentadienyl) complexes with monodentate N-heterocyclic carbene (NHC) ligands bearing a pendant anthracenyl substituent have been shown to undergo intramolecular C-C coupling reactions. Herein, two bidentate NHC ligands substituted with pyridyl or triazolyl donor groups were prepared along with the corresponding MII/III (M = RuII, OsII, RhIII, IrIII) complexes. While the Rh(Cp*) complex featuring an NHC-triazole bidentate ligand underwent the equivalent reaction as the monodentate Rh(NHC) complex, i.e., it formed a polydentate ligand, the pyridyl-pendant derivative was unequivocally shown to be unreactive. This contrasting behavior was further investigated by density functional theory (DFT) calculations that highlighted significant differences between the two types of Rh(III) complexes with pendant pyridyl or triazolyl N-coordinating groups. Modeling of the reaction pathways suggests that the initial formation of a dicationic Rh(III) species is unfavorable and that the internal ligand transformation proceeds first by dissociation of the coordinated N atom of the pendant group from the Rh center. After the formation of a neutral η4-fulvene ligand via combined proton/single electron transfer, a cycloaddition occurs between the exo-ene bond of fulvene and the 9' and 10' positions on the pendant anthracenyl group. The resulting experimental UV-visible spectrum recorded in methanol of the polydentate triazolyl-based Rh species revealed the loss of the vibronic coupling typically associated with an anthracenyl functional group. Moreover, TD-DFT modeling indicates the presence of an equilibrium process whereby the N-coordination of the pendant triazolyl group to the RhIII center appears to be highly labile. Charge decomposition analysis (CDA) of the DFT-modeled species with the dissociated triazolyl group revealed a pseudo-η3-allylic interaction between the π-type MOs of the transformed anthracenyl group and the RhIII center; thus, the singly attached chelating ligand is classified as having rare nonadenticity.

Impact of Coordination Mode and Ferrocene Functionalization on the Anticancer Activity of N-Heterocyclic Carbene Half-Sandwich Complexes.

The substitution of phenyl rings in established drugs with ferrocenyl moieties has been reported to yield compounds with improved biological activity and alternative modes of action, often involving the formation of reactive oxygen species (ROS). Translating this concept to N-heterocyclic carbene (NHC) complexes, we report here organometallics with a piano-stool structure that feature di- or tridentate ligand systems. The ligands impacted the cytotoxic activity of the NHC complexes, but the coordination modes seemed to have a limited influence, which may be related to the propensity of forming the same species in solution. In general, the stability of the complexes in an aqueous environment and their reactivity to selected biomolecules were largely dominated by the nature of the metal center. While the complexes promoted the formation of ROS, the levels did not correlate with their cytotoxic activity. However, the introduction of ferrocenyl moieties had a significant impact on the antiproliferative potency of the complexes and, in particular, some of the ferrocenyl-functionalized compounds yielded IC50 values in the low µM range.

Haber-independent, asymmetric synthesis of the marine alkaloid epi-leptosphaerin from a chitin-derived chiral pool synthon.

Chitin-derived platforms are emerging as valuable chemical entities for the construction of nitrogenous fine chemicals in processes independent of Haber ammonia. However, much of the work in this area has focused on achiral platforms that limit routine entry into enantiopure, bio-based N-chemical space. Herein, dihydroxyethyl acetamidofuran (Di-HAF), a chiral synthon readily available from chitin, has been transformed into the marine alkaloid epi-leptosphaerin. This work extends the fledgling Haber-independent synthesis concept to enantiopure chemical space not routinely accessible from existing achiral platforms.

Progress toward a biomimetic synthesis of pegaharmaline A.

Efforts towards a biomimetic synthesis of the alkaloid pegaharmaline A began with attempted validation of the putative biosynthesis described in the isolation report. The reaction between vasicinone-derived pyrroloquinazoline 1 and tryptamines 2 and 9 proceeded under aqueous conditions at ambient temperature, forming the 1,6,10-triazaspiro[4.5]dec-7-anes 7 and 8. Alternative pyrroloquinazoline precursors were subsequently investigated; the reaction between dehydrodimethylisovasicinone (10) and tryptamine (9) led to the ring-opened product 13 that could not be converted into pegaharmaline A scaffold under Bischler-Napieralski conditions. The Pictet-Spengler reaction between a model isovasicinone (22) and tryptamine (9) was successful, but the resulting tetrahydro-ß-carboline could not be converted into the natural product. These studies suggest an alternative biosynthetic pathway is potentially operating, while structural revision of the natural product cannot be ruled out at this time. As vasicinones and tryptamines are widely distributed throughout Nature, the novel scaffolds reported herein may be undiscovered natural products.

Synthetic Strategy Towards Heterodimetallic Half-Sandwich Complexes Based on a Symmetric Ditopic Ligand.

Multimetallic complexes have been shown in several examples to possess greater anticancer activity than their monometallic counterparts. The increased activity has been attributed to altered modes of action. We herein report the synthesis of a series of heterodimetallic compounds based on a ditopic ligand featuring 2-pyridylimine chelating motifs and organometallic half-sandwich moieties. The complexes were characterized by a combination of 1H NMR spectroscopy, electrospray ionization mass spectrometry, elemental analysis and single crystal X-ray diffraction. Investigations into the stability of representative complexes in DMSO-d 6 and 10% DMSO-d 6 /D2O revealed the occurrence of solvent-chlorido ligand exchange. Proliferation assays in four human cancer cell lines showed that the Os-Rh complex possessed minimal activity, while all other complexes were inactive.

Octacycles and Nonacycles from 3-Hydroxy-2,2'-bisindole.

3-Hydroxy-2,2'-bisindole undergoes acid- and base-mediated dimerization-skeletal rearrangement processes, generating polyheterocyclic ring systems containing up to nine rings. The mechanistic rationale for these reactions is provided, which infers some overlap with the previously reported reactivity of 3',3″-dihydroxytetraindole under analogous reaction conditions.

Triazolyl-Functionalized N-Heterocyclic Carbene Half-Sandwich Compounds: Coordination Mode, Reactivity and in†vitro Anticancer Activity.

We report investigations on the anticancer activity of organometallic [MII/III (η6 -p-cymene/η5 -pentamethylcyclopentadienyl)] (M=Ru, Os, Rh, and Ir) complexes of N-heterocyclic carbenes (NHCs) substituted with a triazolyl moiety. Depending on the precursors, the NHC ligands displayed either mono- or bidentate coordination via the NHC carbon atom or as N,C-donors. The metal complexes were investigated for their stability in aqueous solution, with the interpretation supported by density functional theory calculations, and reactivity to biomolecules. In vitro cytotoxicity studies suggested that the nature of both the metal center and the lipophilicity of the ligand determine the biological properties of this class of compounds. The IrIII complex 5 d bearing a benzimidazole-derived ligand was the most cytotoxic with an IC50 value of 10 µM against NCI-H460 non-small cell lung carcinoma cells. Cell uptake and distribution studies using X-ray fluorescence microscopy revealed localization of 5 d in the cytoplasm of cancer cells.

Heptadentate, Octadentate, Or Even Nonadentate? Denticity in the Unexpected Formation of an All-Carbon Donor-Atom Ligand in RhIII(Cp*)(Anthracenyl-NHC) Complexes.

Investigations on incorporating an N-flanking anthracenyl moiety to [Rh(Cp*)(NHC)Cl2] complexes surprisingly led to the formation of an intramolecular C-C bond between the Cp* and anthracenyl moieties, with additional auxiliary interactions between the metal and the anthracenyl ring system. In silico modeling supports a reaction mechanism whereby Rh(η4-tetramethylfulvene) intermediates undergo metallocycloaddition and the abstraction of a chlorido ligand, affording unique cationic complexes that feature Rh centers coordinated by a nonadentate ligand with exclusively carbon donor atoms. Some Rh-C interactions were extremely weak but nevertheless exhibited covalent bonding character. These weak Rh-C interactions were readily displaced by stronger electron donors, and the nonadentate ligand reverted to the heptadentate coordination mode observed in the intermediate. As far as we are aware, this study provides the first conclusive evidence of complexes bearing a single nonadentate κ9-coordinating ligand that features only carbon donors bound to a metal center.

Impact of the Metal Center and Leaving Group on the Anticancer Activity of Organometallic Complexes of Pyridine-2-carbothioamide.

RuII(cym)Cl (cym = η6-p-cymene) complexes of pyridinecarbothioamides have shown potential for development as orally active anticancer metallodrugs, underlined by their high selectivity towards plectin as the molecular target. In order to investigate the impact of the metal center on the anticancer activity and their physicochemical properties, the Os(cym), Rh- and Ir(Cp*) (Cp* = pentamethylcyclopentadienyl) analogues of the most promising and orally active compound plecstatin 2 were prepared and characterized by spectroscopic techniques and X-ray diffraction analysis. Dissolution in aqueous medium results in quick ligand exchange reactions; however, over time no further changes in the 1H NMR spectra were observed. The Rh- and Ir(Cp*) complexes were investigated for their reactions with amino acids, and while they reacted with Cys, no reaction with His was observed. Studies on the in vitro anticancer activity identified the Ru derivatives as the most potent, independent of their halido leaving group, while the Rh derivative was more active than the Ir analogue. This demonstrates that the metal center has a significant impact on the anticancer activity of the compound class.

High Antiproliferative Activity of Hydroxythiopyridones over Hydroxypyridones and Their Organoruthenium Complexes.

Hydroxypyr(id)ones are a pharmaceutically important class of compounds that have shown potential in diverse areas of drug discovery. We investigated the 3-hydroxy-4-pyridones 1a-1c and 3-hydroxy-4-thiopyridones 1d-1f as well as their Ru(η6-p-cymene)Cl complexes 2a-2f, and report here the molecular structures of 1b and 1d as determined by X-ray diffraction analysis. Detailed cell biological investigations revealed potent cytotoxic activity, in particular of the 3-hydroxy-4-thiopyridones 1d-1f, while the Ru complexes of both compound types were less potent, despite still showing antiproliferative activity in the low µM range. The compounds did not modulate the cell cycle distribution of cancer cells but were cytostatic in A549 and cytotoxic in NCI-H522 non-small lung cancer cells, among other effects on cancer cells.

Synthetic Studies toward Bisindigotin: Polyheteroaromatic Scaffolds via Skeletal Rearrangements of a Diacetoxytetraindole.

The deacetylation of a diacetoxytetraindole formed the basis of a first-generation synthetic route toward the alkaloid bisindigotin. However, this conceptually straightforward plan led to unexpected results. Acid-mediated hydrolysis initiated skeletal rearrangement processes that resulted in the formation of two novel heteroaromatic scaffolds, both of which contain nine rings. Upon treating the same diacetoxytetraindole with base followed by a silica-mediated autoxidation, a distinct cascade process occurred, generating another novel scaffold also comprising nine rings. A mechanistic rationale for these observations is provided.

The Synthesis and Mechanistic Considerations of a Series of Ammonium Monosubstituted H-Phosphonate Salts.

A series of ammonium monosubstituted H-phosphonate salts were synthesized by combining H-phosphonate diesters with amines in the absence of solvent at 80 °C. Variation of the ester substituent and amine produced a range of ionic liquids with low melting points. The products and by-products were analyzed by spectroscopic and spectrometric techniques in order to get a better mechanistic picture of the dealkylation and formal dearylation observed. For dialkyl H-phosphonate diesters, (RO)2 P(O)H (R=alkyl), the reaction proceeds via direct dealkylation with the reactivity increasing in the order R=iPr

The photophysical properties of naphthalene bridged disilanes.

Structural isomers of naphthalene-bridged disilanes were prepared via catalytic intramolecular dehydrocoupling of disilyl precursors using Wilkinson's catalyst. Interestingly, it was observed that interchanging the side groups on the silicon atoms altered the photophysical properties of the bridged disilanes. Herein, we report the first example of naphthalene bridged disilanes forming excimers in non-polar solvents. Cyclic voltammetry experiments and DFT calculations were performed to analyse the band gaps of the compounds and σ-π mixing in the bridged disilanes.