Marco M. Allard

Comparative Activities of Nickel(II) and Zinc(II) Complexes of Asymmetric [NN'O] Ligands as 26S Proteasome Inhibitors

In this study, we compare the proteasome inhibition capabilities of two anticancer candidates, [Ni(L(IA))(2)] (1) and [Zn(L(IA))(2)] (2), where L(IA-) is the deprotonated form of the ligand 2,4-diiodo-6-(((2-pyridinylmethyl)amino)methyl)phenol. Species 1 contains nickel(II), a considerably inert ion that favors covalency, whereas 2 contains zinc(II), a labile transition metal ion that favors predominantly ionic bonds. We report on the synthesis and characterization of 1 and 2 using various spectroscopic, spectrometric, and structural methods. Furthermore, the pharmacological effects of 1 and 2, along with those of the salts NiCl(2) and ZnCl(2), were evaluated in vitro and in cultured human cancer cells in terms of their proteasome-inhibitory and apoptotic cell-death-inducing capabilities. It is shown that neither NiCl(2) nor 1 have the ability to inhibit the proteasome activity at any sustained levels. However, ZnCl(2) and 2 showed superior inhibitory activity versus the chymotrypsin-like activity of both the 26S proteasome (IC(50) = 5.7 and 4.4 micromol/L, respectively) and the purified 20S proteasome (IC(50) = 16.6 and 11.7 micromol/L, respectively) under cell-free conditions. Additionally, inhibition of proteasomal activity in cultured prostate cancer cells by 2 was associated with higher levels of ubiquitinated proteins and apoptosis. Treatment with either the metal complex or the salt was relatively nontoxic toward human normal cells. These results strengthen the current working hypothesis that fast ligand dissociation is required to generate an [ML(IA)](+) pharmacophore, capable of interaction with the proteasome. This interaction, possibly via N-terminal threonine amino acids present in the active sites, renders the proteasome inactive. Our results present a compelling rationale for 2 along with its gallium(III) and copper(II) congeners to be further investigated as potential anticancer drugs that act as proteasome inhibitiors.

Bioinspired Five-Coordinate Iron(III) Complexes for Stabilization of Phenoxyl Radicals†

Considerable effort has been directed towards the integration of biomimetic principles into molecular materials that have customized and controllable properties. The notion of stimulus-triggered molecular switching between two or more ground states of comparable energy is particularly relevant because such switching leads to detectable electronic and structural changes. Coordination complexes that merge transition-metal ions with ligands that stabilize organic radicals are among the most promising candidates for redox-responsive switching processes. Among the electroactive ligands that have been well characterized, those that contain phenolate moieties are significant because of their synthetic versatility and redox accessibility. This importance has been highlighted by studies on metal–phenoxyl complexes that have several geometries. Iron(III) complexes that contain phenolates tend to favor an octahedral geometry and are electrochemically reversible, but usually do not withstand multiple redox cycles. Thus, an understanding of the alternative geometries of such complexes becomes a necessary strategy for the future development of redox switches. We are investigating bioinspired designs that incorporate the basic geometries that are present in redox-versatile enzymes, such as tyrosine hydroxylase and intradiol dioxygenase, in which five-coordinate iron(III) centers support radical-based mechanisms for generating l-3,4-dihydroxyphenylalanine (l-DOPA) and cleaving catechol-type rings, respectively. We have reported the behavior of high-spin iron(III) complexes that are confined to low-symmetry, pentadentate N2O3 environments. [6] In these complexes, the assignment of oxidation states becomes challenging because of the contributions of ligandand metal-centered orbitals to the same redox process, and the presence of five unpaired electrons. Nonetheless, we have shown that high oxidation states are unavailable to the metal ion, and that the ligand supports up to three consecutive oxidations, which leads to antiferromagnetic interactions. Relative to octahedral fields, these fivecoordinate environments are expected to yield low-degeneracy molecular orbitals (MOs) that are sensitive to subtle but noticeable structural changes in the ligands. These changes should lead to orbital rearrangements that modify the sequence by which phenolate oxidations occur. Herein, we investigate the behavior of the five-coordinate species [FeL] (1) and [FeL] (2, Scheme 1), in which a low-symmetry ligand field is purposefully enforced around the 3d metal ion by the N2O3 ligands. Ligands [L ] and [L] both contain N2O3 environments with three phenolate moieties, denoted A, A’, and B; phenolates A and A’ share the same amine group and are chemically equivalent, whereas phenolate B is attached to either an azomethine group in L or to a methylamine group in L. Both species have four accessible ground states: [FeL]/[FeL] , [FeLC], [FeLCC], and [FeLCCC]. The aim of this study is to determine the sequence in which each of the phenolate rings is oxidized in the presence of the azomethine and the methylamine groups, and to test the feasibility of consecutive, multielectronic oxidations by ion-pairing effects with the supporting electrolyte. This study is intended to contribute to the fundamental understanding of the redox and electronic behavior of high-spin 3d 5 ions in five-coordinate ligand fields, and provide significant insight into bioinspired redox cycling. Complexes 1 and 2 were synthesized as previously described and crystals that were suitable for analysis by [*] M. M. Allard, J. A. Sonk, Dr. M. J. Heeg, Prof. H. B. Schlegel, Prof. C. N. Verani Department of Chemistry, Wayne State University 5101 Cass Ave. Detroit, MI 48202 (USA) E-mail: cnverani@chem.wayne.edu Homepage: http://chem.wayne.edu/veranigroup/

Effects of Electronic Mixing in Ruthenium(II) Complexes with Two Equivalent Acceptor Ligands. Spectroscopic, Electrochemical, and Computational Studies

The lowest energy metal to ligand charge transfer (MLCT) absorption bands found in ambient solutions of [Ru(NH(3))(4)(Y-py)(2)](2+) and [Ru(L)(2)(bpy)(2)](+) complexes (Y-py a pyridine ligand and (L)(n) a substituted acetonylacetonate, halide, am(m)ine, etc.) consist of two partly resolved absorption envelopes, MLCT(lo) and MLCT(hi). The lower energy absorption envelope, MLCT(lo), in these spectra has the larger amplitude for the bis-(Y-py) complexes, but the smaller amplitude for the bis-bpy the complexes. Time-dependent density functional theory (TD-DFT) approaches have been used to model 14 bis-bpy, three bis-(Y-py), and three mono-bpy complexes. The modeling indicates that the lowest unoccupied molecular orbital (LUMO) of each bis-(Y-py) complex corresponds to the antisymmetric combination of individual Y-py acceptor orbitals and that the transition involving the highest occupied molecular orbital (HOMO) and LUMO (HOMO-->LUMO) is the dominant contribution to MLCT(lo) in this class of complexes. The LUMO of each bis-bpy complex that contains a C(2) symmetry axis also corresponds largely to the antisymmetric combination of individual ligand acceptor orbitals, while the LUMOs are more complex when there is no C(2) axis; furthermore, the energy difference between the HOMO-->LUMO and HOMO-->LUMO+1 transitions is too small (<1000 cm(-1)) to resolve in the spectra of the bis-bpy complexes in ambient solutions. Relatively weak MLCT(lo) absorption contributions are found for all of the [Ru(L)(2)(bpy)(2)](m+) complexes examined, but they are experimentally best defined in the spectra of the (L)(2) = X-acac complexes. TD-DFT modeling of the HOMO-->LUMO transition of [Ru(L)(4)bpy](m+) complexes indicates that it is too weak to be detected and occurs at significantly lower energy (about 3000-5000 cm(-1)) than the observed MLCT absorptions. Since the chemical properties of MLCT excited states are generally correlated with the HOMO and/or LUMO properties of the complexes, such very weak HOMO-->LUMO transitions can complicate the use of spectroscopic information in their assessment. As an example, it is observed that the correlation lines between the absorption energy maxima and the differences in ground state oxidation and reduction potentials (DeltaE(1/2)) have much smaller slopes for the bis-bpy than the mono-bpy complexes. However, the observed MLCT(lo) and the calculated HOMO-->LUMO transitions of bis-bpy complexes correlate very similarly with DeltaE(1/2) and this indicates that it is the low energy and small amplitude component of the lowest energy MLCT absorption band that is most appropriately correlated with excited state chemistry, not the absorption maximum as is often assumed.

Computational modeling of the triplet metal-to-ligand charge-transfer excited-state structures of mono-bipyridine-ruthenium(II) complexes and comparisons to their 77 K emission band shapes

A computational approach for calculating the distortions in the lowest energy triplet metal to ligand charge-transfer ((3)MLCT = T(0)) excited states of ruthenium(II)-bipyridine (Ru-bpy) complexes is used to account for the patterns of large variations in vibronic sideband amplitudes found in the experimental 77 K emission spectra of complexes with different ancillary ligands (L). Monobipyridine, [Ru(L)(4)bpy](m+) complexes are targeted to simplify analysis. The range of known emission energies for this class of complexes is expanded with the 77 K spectra of the complexes with (L)(4) = bis-acetonylacetonate (emission onset at about 12,000 cm(-1)) and 1,4,8,11-tetrathiacyclotetradecane and tetrakis-acetonitrile (emission onsets at about 21,000 cm(-1)); no vibronic sidebands are resolved for the first of these, but they dominate the spectra of the last two. The computational modeling of excited-state distortions within a Franck-Condon approximation indicates that there are more than a dozen important distortion modes including metal-ligand modes (low frequency; lf) as well as predominately bpy modes (medium frequency; mf), and it simulates the observed 77 K emission spectral band shapes of selected complexes very well. This modeling shows that the relative importance of the mf modes increases very strongly as the T(0) energy increases. Furthermore, the calculated metal-centered SOMOs show a substantial bpy-π-orbital contribution for the complexes with the highest energy T(0). These features are attributed to configurational mixing between the diabatic MLCT and the bpy (3)ππ* excited states at the highest T(0) energies.

Interfacial Behavior and Film Patterning of Redox‐Active Cationic Copper(II)‐Containing Surfactants

Herein, we describe the synthesis and characterization of a novel series of single-tail amphiphiles LPyCn (Py=pyridine, Cn=C18, C16, C14, C10) and their copper(II)-containing complexes, which are of relevance for patterned films. The N-(pyridine-2-ylmethyl)alkyl-1-amine ligands and their complexes [CuIICl2(LPyC18)] (1), [CuIICl2(LPyC16)] (2), [CuIICl2(LPyC14)] (3), [CuIIBr2(LPyC18)] (4), [CuIIBr2(LPyC16)] (5), and [CuIIBr2(LPyC10)] (6) were synthesized, isolated, and characterized by means of mass spectrometry, IR and NMR spectroscopies, and elemental analysis. Complexes 1, 2, 3, and 6 had their molecular structure solved by X-ray diffraction methods, which showed that the local geometry around the metal center is distorted square planar. With the aim of using these species as precursors for redox-responsive films, an assessment of their electrochemical properties involved cyclic voltammetry in different solvents, with different supporting electrolytes and scan rates. Density functional theory calculations of relevant species in bulk and at interfaces were used to evaluate their electronic structure and dipole moments. The morphology and order of the resulting films at the air/water interface were studied by isothermal compression and Brewster angle microscopy. Biphasic patterned Langmuir films were observed for all complexes except 3 and 6, and dependence on the chain length and the nature of the halogen coligand determine the characteristics of the isotherms and their intricate topology. Complexes 3 and 6, which have shorter chain lengths, failed to exhibit organization. These results exemplify the first comprehensive study of the behavior of single-tail metallosurfactants, which are likely to lead to high-end technological applications based on their patterned films.

A modular approach to redox-active multimetallic hydrophobes of discoid topology.

A new modular [Fe(II)(Fe(III)L(2))(3)](PF(6))(2) species with discoid (disk-like) topology exhibits redox and surfactant properties and points to a new approach for multimetallic Langmuir film precursors.

Investigation of the Electronic, Photosubstitution, Redox, and Surface Properties of New Ruthenium(II)-Containing Amphiphiles

A series of pyridine- and phenol-based ruthenium(II)-containing amphiphiles with bidentate ligands of the following types are reported: [(L(PyI))Ru(II)(bpy)(2)](PF(6))(2) (1), [(L(PyA))Ru(II)(bpy)(2)](PF(6))(2) (2), [(L(PhBuI))Ru(II)(bpy)(2)](PF(6)) (3), and [(L(PhClI))Ru(II)(bpy)(2)](PF(6)) (4). Species 1 and 2 are obtained by treatment of [Ru(bpy)(2)Cl(2)] with the ligands L(PyI) (N-(pyridine-2-ylmethylene)octadecan-1-amine) and L(PyA) (N-(pyridine-2-ylmethyl)octadecan-1-amine). The imine species 3 and 4 are synthesized by reaction of [Ru(bpy)(2)(CF(3)SO(3))(2)] with the amine ligands HL(PhBuA) (2,4-di-tert-butyl-6-((octadecylamino)methyl)phenol), and HL(PhClA) (2,4-dichloro-6-((octadecylamino)methyl)phenol). Compounds 1-4 are characterized by means of electrospray ionization (ESI(+)) mass spectrometry, elemental analyses, as well as electrochemical methods, infrared and UV-visible absorption and emission spectroscopies. The cyclic voltammograms (CVs) of 1-2 are marked by two successive processes around -1.78 and -2.27 V versus Fc(+)/Fc attributed to bipyridine reduction. A further ligand-centered reductive process is seen for 1. The Ru(II)/Ru(III) couple appears at 0.93 V versus Fc(+)/Fc. The phenolato-containing 3 and 4 species present relatively lower reduction potentials and more reversible redox behavior, along with Ru(II/III) and phenolate/phenoxyl oxidations. The interpretation of observed redox behavior is supported by density functional theory (DFT) calculations. Complexes 1-4 are surface-active as characterized by compression isotherms and Brewster angle microscopy. Species 1 and 2 show collapse pressures of about 29-32 mN·m(-1), and are strong candidates for the formation of redox-responsive monolayer films.

Electronic and interfacial behavior of gemini metallosurfactants with copper(II)/pseudohalide cascade cores

In this paper we discuss the newly synthesized binuclear species [Cu2(L(PY18))2(μ1,1-N3)2(N3)2] (1) and [Cu2(L(PY18))2(μ1,3-SCN)2(NCS)2] (2), as obtained from the monometallic precursor [Cu(L(PY18))Br2]. These gemini metallosurfactants incorporate metal/anion cascade cores and are investigated by experimental and theoretical methods. Diagnostic IR stretches support the presence of μ1,1-bridged (end-on, 2075 cm(-1)) azide groups in 1 and μ1,3-bridged (end-to-end, 2117 cm(-1)) thiocyanate groups in 2. Anion-to-copper LMCT electronic processes at 390 and 440 nm for 1 and at 415 nm for 2 reinforce the nature of the metal/anion cascade cores. Both species are redox-active, magnetically uncoupled due to poor orbital overlap, and robust in the presence of strongly coordinating solvents. At the air-water interface, 1 and 2 yield Langmuir films with high collapse pressures of ca. 60 mN m(-1). Domain formation is considerably less extensive than that observed for the related monometallic precursor and the average molecular areas are in good agreement with their modeled molecular size. The resulting Langmuir-Blodgett films are isolated on silica substrates and investigated using IR-reflectance/absorbance spectroscopy.