Synthesis of Migrastatin Analogues as Inhibitors of Tumour Cell Migration: Exploring Structural Change in and on the Macrocyclic Ring.

Migrastatin and isomigrastatin analogues have been synthesised in order to contribute to structure-activity studies on tumour cell migration inhibitors. These include macrocycles varying in ring size, functionality and alkene stereochemistry, as well as glucuronides. The synthesis work included application of the Saegusa-Ito reaction for regio- and stereoselective unsaturated macroketone formation, diastereoselective Brown allylation to generate 9-methylmigrastatin analogues and chelation-induced anomerisation to vary glucuronide configuration. Compounds were tested in vitro against both breast and pancreatic cancer cell lines and inhibition of tumour cell migration was observed in both wound-healing (scratch) and Boyden chamber assays. One unsaturated macroketone showed low affinity for a range of secondary drug targets, indicating it is at low risk of displaying adverse side effects.

Synthesis of Migrastatin Analogues as Inhibitors of Tumour Cell Migration: Exploring Structural Change in and on the Macrocyclic Ring.

Invited for the cover of this issue are Paul V. Murphy and co-workers at the National University of Ireland Galway (NUI Galway) and Warsaw University. The image depicts MGSTA-6 giving a stop signal to tumour cells that are on the move. Read the full text of the article at 10.1002/chem.201502861.

What controls the magnetic interaction in bis-µ-alkoxo Mn(III) dimers? A combined experimental and theoretical exploration.

The synthesis and magnetic characterisation of a series of bis-µ-alkoxide bridged Mn(III) dinuclear complexes of general formula [Mn(III)(2)(µ-OR)(2)(biphen)(2)(ROH)(x)(L)(y)] (where R = Me, Et; H(2) biphen = 2,2'-biphenol and L = terminally bonded N-donor ligand) is described, doubling the literature basis set for this type of complex. Building on these findings we have categorised all known µ-OR bridged Mn(III) dinuclear complexes into one of three classifications with respect to their molecular structures. We have then employed DFT and MO calculations to assess all potential magneto-structural correlations for this class of compound in order to identify the structural requirements for constructing ferromagnetic family members. Our analysis indicates that the most influential parameter which governs the exchange interaction in this class of compounds is the relative orientation of the JT axes of the Mn(III)  atoms. A perpendicular orientation of the JT axes leads to a large ferromagnetic contribution to the exchange. These results also suggest that a large ferromagnetic interaction and a large anisotropy are unlikely to co-exist in such structural types.

Two heptacopper(II) disk complexes with a [Cu(7)(µ(3)-OH)(4)(µ-OR)(2)](8+) core.

The reaction of CuX(2) (X(-) ≠ F(-)) salts with 1 equiv of 3-pyridyl-5-tert-butylpyrazole (HL) in basic methanol yields blue solids, from which disk complexes of the type [Cu(7)(µ(3)-OH)(4)(µ-OR)(2)(µ-L)(6)](2+) and/or the cubane [Cu(4)(µ(3)-OH)(4)(HL)(4)](4+) can be isolated by recrystallization under the appropriate conditions. Two of the disk complexes have been prepared in crystalline form: [Cu(7)(µ(3)-OH)(4)(µ-OCH(2)CF(3))(2)(µ-L)(6)][BF(4)](2) (2) and [Cu(7)(µ(3)-OH)(4)(µ-OCH(3))(2)(µ-L)(6)]Cl(2)·xCH(2)Cl(2) (3·xCH(2)Cl(2)). The molecular structures of both compounds as solvated crystals can be described as [Cu⊂Cu(6)(µ-OH)(4)(µ-OR)(2)(µ-L)(6)](2+) (R = CH(2)CF(3) or CH(3)) adducts. The [Cu(6)(µ-OH)(4)(µ-OR)(2)(µ-L)(6)] ring is constructed of six square-pyramidal Cu ions, linked by 1,2-pyrazolido bridges from the L(-) ligands and by basal, apical-bridging hydroxy or alkoxy groups, while the central Cu ion is bound to the four metallamacrocyclic hydroxy donors in a near-regular square-planar geometry. The L(-) ligands project above and below the metal ion core, forming two bowl-shaped cavities that are fully (R = CH(2)CF(3)) or partially (R = CH(3)) occupied by the alkoxy R substituents. Variable-temperature magnetic susceptibility measurements on 2 demonstrated antiferromagnetic interactions between the Cu ions, yielding a spin-frustrated S = (1)/(2) magnetic ground state that is fully populated below around 15 K. Electrospray ionization mass spectrometry, UV/vis/near-IR, and electron paramagnetic resonance measurements imply that the heptacopper(II) disk motif is robust in organic solvents.

Proline derived guanidine catalysts forge extensive H-bonded architectures: a solution and solid state study.

The preparation of a range of amino acid derived guanidine organocatalysts is reported together with their application to the Michael addition of 2-hydroxy-1,4-napthoquinone to ß-nitrostyrene, achieving a maximum ee of 56%. Some insight into the mechanism was sought by using X-ray crystallography and a detailed study of the intra- and intermolecular hydrogen bonding is reported.

A cobalt metallacrown anion host with guest-dependent redox activity.

Two bowl-shaped cavities, each having three OH(-) hydrogen-bond donors at its base, are present in double-cone-shaped metallacrown anion host [Co(6)(mu-OH)(6)(mu-L)(6)](m+) (1(m+); HL=3{5}-(pyrid-2-yl)-5{3}-(tert-butyl)pyrazole). Depending on its affinity for the anions present, it can be isolated in its Co(III) (3)Co(II) (3) (m=3; e.g., 1(ClO(4))(3)) and Co(III) (2)Co(II) (4) (m=2; e.g., 1(BF(4))(2)n H(2)O) oxidation states. See picture for photographs of isolated salts.Reaction of cobalt(II) salts with one equivalent of 3{5}-(pyrid-2-yl)-5{3}-(tert-butyl)pyrazole (HL) and NaOH in EtOH affords salts of [Co(6)(mu-OH)(6)(mu-L)(6)](m+) (2(m+), m=2 or 3). This is formed from alternating tetrahedral and octahedral cobalt centers, giving a double-cone-shaped molecule with two bowl-shaped cavities. Each cavity has three OH(-) hydrogen-bond donors at its base, giving them an affinity for inorganic anions. Reactions with CoX(2) (X(-)=ClO(4) (-) or CF(3)SO(3) (-)) afford products with the stoichiometry 2X(3). In contrast, when salts of fluorinated anions are used, the products have the formulae 2Y(2)n H(2)O (Y(-)=BF(4) (-), PF(6) (-), or SbF(6) (-); n approximately 2). The connectivity and topology of the metallacrown were confirmed by crystal structures of three of these salts. Magnetic measurements imply that the tricationic products have the oxidation state Co(III) (3)Co(II) (3), while the dications are formulated as Co(III) (2)Co(II) (4). Solutions of 2X(3) contain purely 2(3+) according to NMR spectroscopy, ES mass spectrometry, and UV/Vis/NIR spectroscopy, but solutions of 2Y(2)n H(2)O contain more than one significant component. The 2(3+)/2(2+) couple in MeCN is irreversible at room temperature by cyclic voltammetry, occurring near -1.1 V versus ferrocene/ferrocenium. Importantly, the 2Y(2)n H(2)O compounds do not exhibit this process in the presence of 0.1 M [NBu(4)][BPh(4)] as base electrolyte, but they do show it when the appropriate [NBu(4)]Y salt is used (where the Y(-) ions are present in 10(3)-fold excess). Conversely, the 2X(3) complexes exhibit a strong 2(3+)/2(2+) reduction under both experimental conditions. Hence, the isolation of 2(3+) or 2(2+) in the presence of different anions appears to be controlled by the affinity of those anions for the metallacrown.

Ferromagnetic Ni(II) discs.

A family of planar disc-like hexa-, octa- and decametallic Ni(II) complexes exhibit dominant ferromagnetic exchange. The deca- and octametallic clusters [Ni(II) (10)(tmp)(2)(N(3))(8)(acac)(6)(MeOH)(6)] (1, H(3)tmp=1,1,1-tris(hydroxymethyl)propane; acac=acetylacetonate) and [Ni(II) (8)(thme)(2)(O(2)CPh)(4)(Cl)(6)(MeCN)(6)(H(2)O)(2)] (2, H(3)thme=1,1,1-tris(hydroxymethyl)ethane) represent rare examples of Ni(II)-based single-molecule magnets, and [Ni(II) (10)] (1) possesses the largest barrier to magnetisation reversal of any Ni(II) single-molecule magnet to date.

1D chains of Mn6 single-molecule magnets.

Use of the dicarboxylates iso-phthalate and succinate in the preparation of [Mn(6)] SMMs links the hexametallic units into 1D chains.

Elucidating cylindrospermopsin toxicity via synthetic analogues: An in vitro approach.

Cylindrospermopsin (CYN) is an alkaloid biosynthesized by selected cyanobacteria, the cyto- and genotoxic properties of which have been studied extensively by in vitro and in vivo experimental models. Various studies have separately established the role of uracil, guanidine and hydroxyl groups in CYN-induced toxicity. In the present study, we have prepared five synthetic analogues that all possess a uracil group but had variations in the other functionality found in CYN. We compared the in vitro toxicity of these analogues in common carp hepatocytes by assessing oxidative stress markers, DNA fragmentation and apoptosis. All the analogues tested induced generation of reactive oxygen species, lipid peroxidation (LPO) and DNA fragmentation. However, the greatest increase in LPO and increase in caspase-3 activity, an apoptosis marker, was demonstrated by an analogue containing guanidine, hydroxyl and uracil functionalities similar to those found in CYN but lacking the complex tricyclic structure of CYN. We also report a crystal structure of an analogue lacking the hydroxyl group found in CYN which does not show intramolecular H-bonding interactions between the guanidine and the uracil functionalities. The observations made in this work supports the hypothesis that CYN toxicity is a result of an interplay between both of the uracil, hydroxyl and guanidine functional groups.

Crowding out: ligand modifications and their structure directing effects on brucite-like {Mx(µ3-OH)y} (M = Co(ii), Ni(ii)) core growth within polymetallic cages.

Previous employment of the ligands 2-methoxy-6-[(methylimino)methyl]phenol (L1H) and 2-methoxy-6-[(phenylimino)methyl]phenol (L2H) has resulted in the self-assembly of pseudo metallocalix[6]arene complexes of general formulae: [M7(µ3-OH)6(Lx)6](NO3)y (M = Ni(ii), x = 1, y = 2 (1) and Co(ii/iii), x = 2, y = 3 (2)). Extrapolating upon this work, we report the coordination chemistry of ligands 2-methoxy-6-{[(2-methoxyphenyl)imino]methyl}phenol (L3H), 2-[(benzylimino)methyl]-6-methoxyphenol (L4H), 2-[(benzylamino)methyl]-6-methoxyphenol (L5H) and 2-[(benzylamino)methyl]-4-bromo-6-methoxyphenol (L6H), whose structures are modifications of ligands L1-2H. These ligands are employed in the synthesis and characterisation of the dimetallic complex [Ni(ii)2(L3)3(H2O)](NO3)·2H2O·3MeOH (3); the monometallic complexes [Ni(ii)(L4)2] (4) and [Co(iii)(L4)3]·H2O·MeOH (5a); and the tetranuclear pseudo metallocalix[4]arene complexes: [(NO3)⊂Co(ii)4(µ3-OH)2(L5)4(H2O)2](NO3)·H2O (6), [(NO3)⊂Ni(ii)4(µ3-OH)2(L5)4(H2O)2](NO3)·H2O (7) and [Ni(ii)4(µ3-OH)2(L6)4(NO3)2]·MeCN (8). The tetrametallic 'butterfly' core topologies in 6-8 are discussed with respect to their structural and topological relationship with their heptanuclear [M7] (M = Co(ii), Ni(ii)) pseudo metallocalix[6]arene ancestors (1 and 2).

Mono- and ditopic hydroxamate ligands towards discrete and extended network architectures.

A family of mono- and ditopic hydroxamic acids has been employed in the synthesis and structural and physical characterisation of discrete (0D) and (1- and 2-D) extended network coordination complexes. Examples of the latter include the 1-D coordination polymer {[Zn(ii)(L3H)2]·2MeOH}n (5; L3H2 = 2-(methylamino)phenylhydroxamic acid) and the 2-D extended network {[Cu(ii)(L2H)(H2O)(NO3)]·H2O}n (5; L2H2 = 4-amino-2-(acetoxy)phenylhydroxamic acid). The 12-MC-4 metallacrown [Cu(ii)5(L4H)4(MeOH)2(NO3)2]·3H2O·4MeOH (7) represents the first metal complex constructed using the novel ligand N-hydroxy-2-[(2-hydroxy-3-methoxybenzyl)amino]benzamide (L4H3). Variable temperature magnetic susceptibility studies confirm strong antiferromagnetic exchange between the Cu(ii) centres in 7. Coordination polymer 5 shows photoluminescence in the blue region (λPL∼ 421-450 nm) with a bathochromic shift of the emission (∼15-30 nm) from solution to the solid state.

Enhancing SMM properties via axial distortion of Mn(III)3 clusters.

Replacement of carboxylate and solvent with facially capping tripodal ligands enhances the single-molecule magnet (SMM) properties of [Mn(III)3] triangles.

Molecular Pac-Man and Tacos: layered Cu(II) cages from ligands with high binding site concentrations.

The in situ formation and subsequent Cu(ii) ligation of the polydentate pro-ligands o-[(E)-(2-hydroxy-3-methoxyphenyl)methylideneamino]benzohydroxamic acid (L1H3), o-[(E)-(2-hydroxy-3-methoxy-5-bromophenyl)methylideneamino]benzohydroxamic acid (L2H3) and o-[(E)-(2-hydroxyphenyl)methylideneamino]benzohydroxamic acid (L3H3), leads to the self-assembly of the cages [Cu(ii)10(L1)4(2-aph)2(H2O)2](ClO4)4·5MeOH (), [Cu(ii)14(L1)8(MeOH)2.5(H2O)7.5](NO3)4·3MeOH·7H2O (), [Cu(ii)14(L2)8(MeOH)4(H2O)6](NO3)4·6H2O (), [Cu(ii)14(L3)8(MeOH)6(H2O)2](NO3)4·4MeOH·8H2O () and [Cu(ii)30O(OH)4(OMe)2(L1)16(MeOH)4(H2O)2](ClO4)4·2MeOH·30H2O (). Each member comprises a highly unusual topology derived from off-set, stacked, near planar layers of polynuclear subunits connected through long Cu(ii)-O contacts. The exact topology observed is dependent on the specific reaction conditions and methodologies employed. Dc magnetic susceptibility studies on , , and reveals strong antiferromagnetic exchange between the Cu(ii) centres in all siblings. We also present the 1D coordination polymer {[Cu(ii)(L4)]·H2O}n () comprising the pseudo macrocyclic ligand [[2-[(E)-(2-hydroxy-3-methoxy-phenyl)methyleneamino]benzoyl]amino]ethanimidate (L4H2), which is formed upon the incorporation of an MeCN unit at the hydroxamate group of precursor ligand L1H3.

New routes to high nuclearity cages: a fluoride-based hexaicosametallic manganese cage.

The reaction of MnF3 with benzotriazole (BTAH) in hot MeOH gives the Mn(III) complex [Mn26O16(OH)10(OMe)6(F)10(BTA)20(BTAH)2(MeOH)13(H2O)] which displays hysteresis and temperature-independent magnetisation relaxation at low temperature.

Homo- and heterometallic planes, chains and cubanes.

The synthesis, structural and magnetic characterisation of a family of homo- and heterometallic complexes constructed with the Schiff base ligands 2-iminomethyl-6-methoxy-phenol (L1H) and 2-imino-6-methoxy-phenol (L2H), are discussed. Members include the heterometallic tetranuclear complexes of general formula [Na2M2(X)2(L1)4(Y)2] (where M = Fe(III), X = (-)OMe, Y = NO3(-) (1) and M = Ni(II), X = N3(-) and Y = MeCN (2)), each possessing a butterfly-like topology. We also report the formation of the heterometallic molecular cage [Na3Ni2(L1)6](ClO4) (3) whose metallic skeleton describes a [rare] trigonal bipyramid, the homometallic 1-D coordination polymer [Mn(L1)2(Cl)]n (4), and the tetranuclear cubane clusters [Mn(III)3Mn(IV)(O)3(OEt)(OAc)3(L1)3] (5) and [Ni4(µ3-OMe)4(L2)4(MeOH)4] (6). Dc and ac magnetic susceptibility studies on complexes 5 and 6 reveal S = 9/2 and S = 4 spin ground states.

Synthetic, structural, spectroscopic and theoretical study of a Mn(III)-Cu(II) dimer containing a Jahn-Teller compressed Mn ion.

The heterobimetallic complex [Cu(II)Mn(III)(L)(2)(py)(4)](ClO(4))·EtOH (1) built using the pro-ligand 2,2'-biphenol (LH(2)), contains a rare example of a Jahn-Teller compressed Mn(III) centre. Dc magnetic susceptibility measurements on 1 reveal a strong antiferromagnetic exchange between the Cu(II) and Mn(III) ions mediated through the phenolate O-atoms (J = -33.4 cm(-1)), with magnetisation measurements at low temperatures and high fields suggesting significant anisotropy. Simulations of high-field and high frequency powder EPR data suggest a single-ion anisotropy D(Mn(III)) = +4.45 cm(-1). DFT calculations also yield an antiferromagnetic exchange for 1, though the magnitude is overestimated (J(DFT) = -71 cm(-1)). Calculations reveal that the antiferromagnetic interaction essentially stems from the Mn(d(x(2)-y(2)))-Cu(d(x(2)-y(2))) interaction. The computed single-ion anisotropy and cluster anisotropy also correlates well with experiment. A larger cluster anisotropy for the S = 3/2 state compared to the single-ion anisotropy of Mn(III) is rationalised on the basis of orbital mixing and various contributions that arise due to the spin-orbit interaction.

Twisted molecular magnets.

The use of derivatised salicylaldoximes in manganese chemistry has led to the synthesis of a family of approximately fifty hexanuclear ([Mn(III)(6)]) and thirty trinuclear ([Mn(III)(3)]) Single-Molecule Magnets (SMMs). Deliberate, targeted structural distortion of the metallic core afforded family members with increasingly puckered configurations, leading to a switch in the pairwise magnetic exchange from antiferromagnetic to ferromagnetic. Examination of both the structural and magnetic data revealed a semi-quantitative magneto-structural correlation, from which the factors governing the magnetic properties could be extracted and used for predicting the properties of new family members and even more complicated structures containing analogous building blocks. Herein we describe an overview of this extensive body of work and discuss its potential impact on similar systems.

Investigating the solid state hosting abilities of homo- and hetero-valent [Co7] metallocalix[6]arenes.

A family of homo-valent [Co(II)(7)(OH)(6)(L(1))(6)](NO(3))(2) (1), [(MeOH)(2) is a subset of Co(II)(7)(OH)(6)(L(1))(6)](NO(3))(2) (2) (where L(1)H = 2-iminomethyl-6-methoxyphenol) and hetero-valent [(NO(3))(2) is a subset of Co(III)Co(II)(6)(OH)(6)(L(2))(6)](NO(3))·3MeCN (4) (where L(2)H = 2-iminophenyl-6-methoxyphenol) complexes possess metallic skeletons describing planar hexagonal discs. Their organic exteriors form double-bowl shaped topologies, and coupled with their 3-D connectivity, this results in the formation of molecular cavities in the solid state. These confined spaces are shown to behave as host units in the solid state for guests including solvent molecules and charge balancing counter anions. Magnetic susceptibility measurements on 2 and 4 reveal weak ferro- and ferrimagnetism, respectively. The utilisation of other Co(II) salt precursors gives rise to entirely different species including the mononuclear and trinuclear complexes [Co(II)(L(2))(2)] (5) and [Co(III)(2)Na(I)(1)(L(3))(6)](BF(4)) (6) (where L(3)H = 2-iminomethyl-4-bromo-6-methoxyphenol).

Ferromagnetic exchange in a twisted, oxime-bridged [Mn(III)2] dimer.

The dimeric complex [Mn(III)(2)(Naphth-sao)(2)(Naphth-saoH)(2)(MeOH)(2)]·4MeOH (1·4MeOH), acts as a simple model complex with which to examine the magneto-structural relationship in polymetallic, oxime-bridged Mn(III) complexes. Dc magnetic susceptibility studies reveal that ferromagnetic exchange is mediated through the heavily twisted Mn-O-N-Mn moiety (J = +1.24 cm(-1)) with magnetisation measurements at low temperatures and high fields suggesting significant anisotropy. Simulations of high field, high frequency EPR data reveal a single ion anisotropy, D((Mn(III))) = -3.94 cm(-1). Theoretical studies on simplified model complexes of 1 reveal that calculated values of the exchange coupling and the anisotropy are in excellent agreement with experiment, with the weak ferromagnetism resulting from an accidental orthogonality between the Mn-N-O plane of the first Mn(III) ion and the Jahn-Teller axis of the second Mn(III) ion.