Martinus C. Feiters

From simple to supramolecular cytochrome P450 mimics

Cytochrome P450 is one of Nature’s oxidative workhorses and is utilized in a wide variety of roles, one of the most important being the detoxification of foreign bodies within the liver. As a result of its fundamental importance it has been extensively investigated, modeled and mimicked over the past 30 years, and more recently modified and mutated. During this period the complexity, beauty and activity of the biomimetic model systems developed in the laboratory have grown considerably. The synthetic analogues of the cytochrome P450 system have evolved dramatically from simple sterically hindered porphyrin models through to more complex model systems combining cavities such as cyclodextrins and utilizing the interactions between host and guest to generate substrate selectivity and stereoselectivity in product formation. More recently, researchers have tried to combine knowledge obtained from the developing field of supramolecular chemistry and from biochemistry to construct self-assembling systems that contain all the components of the natural system and even utilize molecular oxygen as the oxidant. These systems are successful in that they can achieve turnover numbers comparable to those observed for the natural system. The history of these developments and the current ‘state-of-the-art’ in construction of mimics of the natural enzyme will be presented.

N-Hydroxyphthalimide/Cobalt(II) Catalyzed Low Temperature Benzylic Oxidation Using Molecular Oxygen

Abstract A variety of (substituted) aryl glyoxylates is formed in good to excellent yield under very mild conditions by direct oxidation of the corresponding arylacetic esters or mandelic acid esters with molecular oxygen and N-hydroxyphthalimide/cobalt(II) acetate as catalyst. Heteroaromatic analogs are more difficult to oxidize with this system. The effect of substitution in the aromatic ring of N-hydroxyphthalimide on the oxidation of ethylbenzene has been studied. Electron withdrawing substituents accelerate the oxidation of ethylbenzene and promote the formation of acetophenone. Electron donating substituents lead to decreased rates of oxidation and enhance the selectivity for 1-phenylethanol.

Toward nanomolar detection by NMR through SABRE hyperpolarization.

SABRE is a nuclear spin hyperpolarization technique based on the reversible association of a substrate molecule and para-hydrogen (p-H2) to a metal complex. During the lifetime of such a complex, generally fractions of a second, the spin order of p-H2 is transferred to the nuclear spins of the substrate molecule via a transient scalar coupling network, resulting in strongly enhanced NMR signals. This technique is generally applied at relatively high concentrations (mM), in large excess of substrate with respect to metal complex. Dilution of substrate ligands below stoichiometry results in progressive decrease of signal enhancement, which precludes the direct application of SABRE to the NMR analysis of low concentration (μM) solutions. Here, we show that the efficiency of SABRE at low substrate concentrations can be restored by addition of a suitable coordinating ligand to the solution. The proposed method allowed NMR detection below 1 μM in a single scan.

Glucose sensor utilizing polypyrrole incorporated in track-etch membranes as the mediator

Abstract: Template synthesis inside track-etch membranes is employed to create conducting microtubules of polypyrrole. Within these tubules, glucose oxidase can be adsorbed irreversibly. while retaining its catalytic activity. A glucose sensor is described utilizing the polypyrrole microtubules as mediator. With this sensor glucose can be measured amperometrically in the concentration range I-30 mM. The sensor is highly selective with respect to other substrates and the sensor response is independent of oxygen concentration. Evidence is presented that in the biosensor direct electron transfer may occur between glucose oxidase and the polypyrrole. Keywords: glucose sensor, direct electron transfer, conducting polymer, amperometry, microtubules. INTRODUCTION Biosensors based on oxido-reductases normally detect a substance indirectly, e.g. by measuring the decrease in oxygen concentration or the increase in hydrogen peroxide concentration (Galiatsatos

Cationic Heteroleptic Cyclometalated Iridium(III) Complexes Containing Phenyl-Triazole and Triazole-Pyridine Clicked Ligands

Novel heteroleptic iridium complexes containing the 1-substituted-4-phenyl-1H-1,2,3-triazole (phtl) cyclometalating ligand have been synthesized. The 3+2 Huisgen dipolar cycloaddition method (‘click’ chemistry) was utilized to prepare a class of bidentate ligands (phtl) bearing different substituents on the triazole moiety. By using various ligands (phtl-R1 and pytl-R2) (R1=adamantane, methyl and R2=adamantane, methyl, β-cyclodextrin, ursodeoxycholic acid), we prepared a small library of new luminescent ionic iridium complexes [Ir(phtr-R1)2(pytl-R2)]Cl and report on their photophysical properties. The flexibility of the clicking approach allows a straightforward control on the chemical-physical properties of the complexes by varying the nature of the substituent on the ligand.

Photoinduced electron transfer between metal-coordinated cyclodextrin assemblies and viologens

Two novel tris(bipyridine)ruthenium(II) complexes bearing two and six beta-cyclodextrin binding sites on their ligands have been synthesised and characterised. Complex 1, bearing two cyclodextrins, adopts a conformation in aqueous solution where parts of the aromatic ligands are self-included into the cyclodextrin moieties. This results in a loss of symmetry of the complex and gives rise to a much more complicated 1H NMR spectrum than expected. Photophysical studies indicate that the appended cyclodextrins protect the luminescent ruthenium core from quenching by oxygen, which results in longer excited state lifetimes and higher emission quantum yields compared with the reference compound, the unsubstituted ruthenium tris(bipyridine). Inclusion of suitable guests such as dialkyl-viologens leads to a quenching of the luminescence of the central unit. In these supramolecular donor-acceptor dyads an efficient photoinduced electron transfer from the excited ruthenium moiety (the donor) to the viologen unit (the acceptor) is observed. The alkyl chain length of the acceptor plays an important role on the binding properties; when it exceeds a certain limit the binding becomes strong enough for electron transfer to occur. Interestingly, a viologen with only one long alkyl tail instead of two shows no efficient quenching; this indicates that cooperative interactions between two cyclodextrins binding one viologen are essential to raise the binding constant of the supramolecular dyad.

Organogel formation and molecular imprinting by functionalized gluconamides and their metal complexes

Functionalized gluconamides and their metal complexes are shown to give supramolecular assemblies, in some cases chiral, and to form organogels in a large variety of organic solvents, e.g. methacrylate mixtures which can be polymerized, as well as o-xylene, chloroform, ethyl acetate, ethanol and tetrahydrofuran.

Control of aggregation and tuning of the location of porphyrins in synthetic membranes as mimics for cytochrome P450

The aggregation and location of two series of tetraarylporphyrins in positively and negatively charged bilayers have been examined. Aggregation of the porphyrins can be reduced by introducing pyridinium groups on the porphyrin ring. In the positively charged bilayers, the degree of aggregation of the porphyrins increases with the number of charges on it. The opposite behavior is found in the case of negatively charged bilayers. All the charged porphyrins form face to face type aggregates whereas the uncharged ones form edge to edge type aggregates. Reduction of aggregation can also be achieved by using “picket-fence” type porphyrins which form head to tail aggregates. The location of the porphyrins in the bilayer is also investigated. The charged porphyrins are located near the aqueous interface and the uncharged ones in the hydrophobic part of the bilayer. Picket-fence porphyrin 7 was found to be the most promising candidate for being studied as a catalyst in cytochrome P450 mimics.

Synthesis and binding properties of novel cyclodextrin dimers

The synthesis of three cyclodextrin dimers from the novel building block 3-amino-3-deoxy-heptakis(6-O-tert-butyldimethylsilyl)-s-cyclodextrin is reported. The cyclodextrins are linked with an amide bond on their secondary sides to an ethylene, octamethylene, or a metal binding bipyridyl group. Complexation studies with the substrate 6-(p-toluidino)-2-naphthalenesulfonic acid are presented and discussed.

Third-generation amperometric biosensor for glucose. Polypyrrole deposited within a matrix of uniform latex particles as mediator

Abstract Uniform latex particles and agarose gels are utilized to create porous membranes in which polypyrrole is electrochemically synthesized. Within the pores of these modified membranes glucose oxidase can be adsorbed irreversibly while its catalytic activity is retained. A glucose sensor which has a considerable lifetime under continuous use is constructed from the enzyme membrane. With this sensor glucose can be measured amperometrically in the concentration range 1–60 mM. The sensor response is independent of oxygen concentration.