Matthew P. Akerman

Gold(III) macrocycles: nucleotide-specific unconventional catalytic inhibitors of human topoisomerase I.

Topoisomerase IB (Top1) is a key eukaryotic nuclear enzyme that regulates the topology of DNA during replication and gene transcription. Anticancer drugs that block Top1 are either well-characterized interfacial poisons or lesser-known catalytic inhibitor compounds. Here we describe a new class of cytotoxic redox-stable cationic Au3+ macrocycles which, through hierarchical cluster analysis of cytotoxicity data for the lead compound, 3, were identified as either poisons or inhibitors of Top1. Two pivotal enzyme inhibition assays prove that the compounds are true catalytic inhibitors of Top1. Inhibition of human topoisomerase IIα (Top2α) by 3 was 2 orders of magnitude weaker than its inhibition of Top1, confirming that 3 is a type I-specific catalytic inhibitor. Importantly, Au3+ is essential for both DNA intercalation and enzyme inhibition. Macromolecular simulations show that 3 intercalates directly at the 5′-TA-3′ dinucleotide sequence targeted by Top1 via crucial electrostatic interactions, which include π–π stacking and an Au···O contact involving a thymine carbonyl group, resolving the ambiguity of conventional (drug binds protein) vs unconventional (drug binds substrate) catalytic inhibition of the enzyme. Surface plasmon resonance studies confirm the molecular mechanism of action elucidated by the simulations.

Synthesis, micellisation and interaction of novel quaternary ammonium compounds derived from l-Phenylalanine with 1,2-dipalmitoyl-sn-glycero-3-phosphocholine as model membrane in relation to their antibacterial activity, and their selectivity over human red blood cells

A series of quaternary ammonium compounds (QUATS) derived from l-Phenylalanine have been synthesized and their antibacterial efficiencies were determined against various strains of Gram-positive and Gram-negative bacteria. The antibacterial activity increased with increasing chain length, exhibiting a cut-off effect at C14 for Gram-positive and C12 for Gram-negative bacteria. The l-Phenylalanine QUATS displayed enhanced antibacterial properties with a higher cut-off point compared to their corresponding l-Phenylalanine ester hydrochlorides. The CMC was correlated with the MIC, inferring that micellar activity contributes to the cut-off effect in antibacterial activity. The hemolytic activities (HC50) of the QUATS against human red blood cells were also determined to illustrate the selectivity of these QUATS for bacterial over mammalian cells. In general, the MIC was lower than the HC50, and assessment of the micellar contribution to the antibacterial and hemolytic evaluation in TBS as a common medium confirmed that these QUATS can act as antibacterial, yet non-toxic molecules at their monomer concentrations. The interaction of the QUATS with the phospholipid vesicles (1,2-dipalmitoyl-sn-glycero-3-phosphocholine, DPPC) in the presence of 1-anilino-8-naphthalene sulfonate (ANS) and 1,6-diphenyl-1,3,5-hexatriene (DPH) as fluorescence probes showed that the presence of the quaternary ammonium moiety causes an increase in hydrophobic interactions, thus causing an increase in antibacterial activity.

Coordination behavior of chromone Schiff bases towards the [ReVO]3+ and [ReI(CO)3]+ cores

Herein, we describe the coordination behavior of chromone Schiff bases towards [ReVO]3+ and [ReI(CO)3]+. The reaction between 2-(2-thiolphenyliminomethyl)-4H-chromen-4-one (Htch) and [Re(CO)5Cl] led to fac-[Re(CO)3(bsch)Cl] (1) (bsch = 2-benzothiazole-4H-chromen-4-one). The square pyramidal [ReO(Hns)] (2) {H2ns=bis-[(2-phenylthiolate)iminomethyl]-methyl-1-(2-hydroxyphenyl)prop-2-en-1-one} and octahedral [ReO(OCH3)(PPh3)(Huch)] (3) complexes were isolated from reactions of trans-[ReVOBr3(PPh3)2] with Htch and H3uch [(5Z)-5-((4-hydroxy-2-methoxy-2H-chromen-3-yl)methyleneamino)-6-amino-1,3-dimethylpyrimidine-2,4(1H, 3H)-dione], respectively. The chromone Schiff bases and their metal complexes were fully characterized via NMR-, IR- and UV–Vis spectroscopy, single crystal XRD analysis and conductivity measurements. In addition, DFT studies were conducted to compare selected optimized and experimental parameters of the complexes.

Pyridyl)benzoazole palladium(II) complexes as homogeneous catalysts in hydrogenation of alkenes and alkynes

Reactions of 2-(2-pyridyl)benzimidazole (L1), 2-(2-pyridyl)benzothiazole (L2) and 2-(2-pyridyl)benzoxazole (L3) with either [PdCl2(NCMe)2] or [PdClMe(COD)] produced complexes [(PdCl2(L1)] (1), [(PdCl2(L2)] (2), [(PdCl2(L3)] (3) and [(PdClMe(L1)] (4) in good yields. Treatment of 1 with PPh3 gave the cationic complex [(Pd(L1)ClPPh3]Cl (5), while reactions of 4 with one equiv. of PPh3 and NaBAr4 (Ar = 3,5-(CF3)2C6H3) produced the cationic complex [(Pd(L1)MePPh3]BAr4 (6). Single-crystal X-ray analysis has been used to elucidate the structure of complex 6. The complexes formed active catalysts in hydrogenation reactions of alkenes and alkynes. Hydrogenation of terminal alkenes was accompanied by isomerization to the internal isomers, while alkyne reactions involved a two-step process producing alkenes and the respective alkanes. While the kinetics data and formation of inactive palladium nanoparticles support the homogeneous nature of the active species, mercury drop experiments indicated a possible role of the nanoparticles in the re-generation of the active species.

Synthesis, characterization and electrocatalytic behavior of cobalt and iron phthalocyanines bearing chromone or coumarin substituents

Cobalt and iron phthalocyanines (Pcs) bearing peripherally tetra-substituted chromone (chr) or coumarin (cou) moieties were formulated and characterized by UV–Vis and FTIR spectroscopy, ESI-TOF mass spectrometry, and elemental analysis. The structural elucidations of the ligands, 4-(chromone-7-oxy)phthalonitrile (1) and 4-(4-(trifluoromethyl)-coumarin-7-oxy)phthalonitrile (2) were complemented by NMR spectroscopy and single crystal X-ray analysis (for 1). The redox properties of the complexes were investigated via voltammetry and the subsequent voltammetric assignments were corroborated by UV–Vis spectroelectrochemistry. Each metal complex displayed four redox processes of which their Pc ring oxidations are irreversible and the remaining redox couples are quasi-reversible. Utilizing the respective metallophthalocyanines, modified working electrodes were prepared by electropolymerization and their electrocatalytic activities toward nitrite oxidation were explored. All the metal complexes showed an increase in nitrite oxidation currents and a minor decrease in oxidation potentials which is indicative of electrocatalysis. The trend of electrocatalytic activity was found to be as follows: CoPc–chr (3) > FePc–cou (4) > CoPc–cou (5).

Ring-opening polymerization of ε-caprolactone catalysed by (pyridyl)benzoazole Zn(II) and Cu(II) complexes

This paper describes the synthesis of (pyridyl)benzoazole Zn(II) and Cu(II) complexes and their applications as catalysts in ring-opening polymerization (ROP) of ε-caprolactone (ε-CL). Reactions of 2-(3-pyridyl)-1H-benzimidazole (L1), 2-(2-pyridyl)-1H-benzothiazole (L2) and 2-(2-pyridyl)-1H-benzimidazole (L3) with Zn(II) and Cu(II) acetates produced the corresponding complexes; [Zn2(L1)2(OAc)4)] (1), [Cu2(L1)2(OAc)4] (2), [Zn(L2)(OAc)2)] (3), [Zn(L3)(OAc)2)] (4) and [Cu(L3), (OAc)2)] (5). Molecular structures of complexes 2 and 5a revealed that while L1 adopts a monodentate binding mode, through the pyridyl nitrogen atom, L3 exhibits a bidentate coordination mode. All the complexes formed active catalysts in the ROP of ε-CL to afford moderate molecular weight polymers. The kinetics of the ROP reactions of ε-CL were pseudo-first-order with respect to monomer and catalysts.

Ruthenium(II/IV) complexes with potentially tridentate Schiff base chelates containing the uracil moiety

Herein we report the synthesis and characterization of trans-[RuIICl2(PPh3)3] with potentially tridentate Schiff bases derived from 5,6-diamino-1,3-dimethyl uracil (H2ddd) and two 2-substituted aromatic aldehydes. In the diamagnetic ruthenium(II) complexes, trans-[RuCl(PPh3)2(Htdp)] (1) {H2tdp = 5-((thiophen-3-yl)methyleneamino)-6-amino-1,3-dimethyluracil} and trans-[RuCl(PPh3)2(Hsdp)] (2) {H2sdp = 5-(2-(methylthio)benzylideneamino)-6-amino-1,3-dimethyluracil}, the Schiff base ligands (i.e. Htdp and Hsdp) act as mono-anionic tridentate chelators. Upon reacting 5-(2-hydroxybenzylideneamino)-6-amino-1,3-dimethyluracil (H3hdp) with the metal precursor, the paramagnetic complex, trans-[RuIVCl2(ddd)(PPh3)2] (3), was isolated, in which the bidentate dianionic ddd co-ligand was formed by hydrolysis. The metal complexes were fully characterized via multinuclear NMR-, IR-, and UV–Vis spectroscopy, single crystal XRD analysis and conductivity measurements. The redox properties were probed via cyclic voltammetry with all complexes exhibiting comparable electrochemical behavior with half-wave potentials (E½) at 0.70 V (for 1), 0.725 V (for 2), and 0.68 V (for 3) versus Ag|AgCl, respectively. The presence of the paramagnetic metal center for 3 was confirmed by ESR spectroscopy.

Coordination of di- and triimine ligands at ruthenium(II) and ruthenium(III) centers: structural, electrochemical and radical scavenging studies

Abstract Herein, we explore the coordination of di- and triimine chelators at ruthenium(II) and ruthenium(III) centers. The reactions of 2,6-bis-((4-tetrahydropyranimino)methyl)pyridine (thppy), N1,N2-bis((3-chromone)methylene)benzene-1,2-diamine (chb), and tris-((1H-pyrrol-2-ylmethylene)ethane)amine (H3pym) with trans-[RuIICl2(PPh3)3] afforded the diamagnetic ruthenium(II) complex cis-[RuCl2(thppy)(PPh3)] (1) and the paramagnetic complexes [mer-Ru2(μ-chb)Cl6(PPh3)2] (2), and [Ru(pym)] (3), respectively. The complexes were characterized by IR, NMR, and UV–vis spectroscopy and molar conductivity measurements. The structures were confirmed by single crystal X-ray diffraction studies. The redox properties of the metal complexes were probed via cyclic- and squarewave voltammetry. Finally, the radical scavenging capabilities of the metal complexes towards the NO and 2,2-di(4-tert-octylphenyl)-1-picrylhydrazyl (DPPH) radicals were investigated

Oxorhenium(V) complexes with bidentate carbohydrazide Schiff bases: synthesis, characterization and DNA interaction studies

The respective coordination reactions of trans-[ReOCl3(PPh3)2] with N-[(4-oxo-4H-chromen-3-yl)methylidene]thiophene-2-carbohydrazide (Hchrtc) and N-[1,3-benzothiazol-2-ylmethylidene]thiophene-2-carbohydrazide (Hbztc) afforded two novel oxorhenium(V) complexes, cis-[ReOCl2(chrtc)(PPh3)] (1) and cis-[ReOCl2(bztc)(PPh3)] (2). These metal compounds were elucidated spectroscopically and their solid-state structures determined by single-crystal X-ray diffraction. The redox properties of the metal complexes were probed using cyclic and square wave voltammetry. The DNA interaction capabilities of 1 and 2 were gauged via UV/Vis spectroscopy DNA titrations and gel electrophoresis studies. A correlation is identified between the DNA cleavage observations and the redox potentials of the metal complexes.

Phase pure Ni3S2 and NiS from bis(N′-ethyl-N-piperazinylcarbodithioato-S,S′)–nickel(II) via solvent thermolysis and aerosol assisted chemical vapour deposition

A bis(N′-ethyl-N-piperazinylcarbodithioato-S,S′)–nickel(II) complex was prepared and characterized using infrared spectroscopy, thermogravimetric and elemental analyses. The crystal X-ray structure for bis(N′-ethyl-N-piperazinylcarbodithioato-S,S′)–nickel(II) was determined. The complex was subsequently used as a single source precursor (SSP) for the synthesis of phase pure Ni3S2 and NiS nanoparticles and thin films via hot injection thermolysis and aerosol assisted chemical vapour deposition (AACVD) routes, respectively. For the hot injection thermolysis route, hexadecylamine (HDA) and oleylamine (OLA) were used as capping groups at varying temperatures. Chloroform was used as the solvent in the AACVD experiments. Powder X-ray revealed that the capping group does not change the phase of nanoparticles formed whereas the AACVD technique produced different phases. Variation of temperature did not affect the phase purity of the nanomaterials formed. The morphology of the thin films obtained via AACVD depended largely on the deposition temperature, whereas for the nanoparticles, temperature and the capping group had a significant impact.