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Biomedical subjects

Armido Studer

Publications and source records attributed to Armido Studer.

At least 19 recordsLinked to original sources
PubMed2006

Structural requirements for optimized delivery, inhibition of oxidative stress, and antiapoptotic activity of targeted nitroxides.

Suppression of mitochondrial production of reactive oxygen species is a promising strategy against intrinsic apoptosis typical of degenerative diseases. Stable nitroxide radicals such as 4-hydroxy-2,2,6,6-tetramethyl piperidine-1-oxyl (TEMPOL) and its analogs combine several important features, including recycleability, electron acceptance from respiratory complexes, superoxide dismutase mimicry, and radical scavenging. Although successful in antioxidant protection, their effective concentrations are too high for successful in vivo applications. Recently (J Am Chem Soc 127:12460, 2005), we reported that 4-amino 2,2,6,6-tetramethyl-1-piperidinyloxy, covalently conjugated to a five-residue segment of gramicidin S (GS), was integrated into mitochondria and blocked actinomycin D (ActD)-induced superoxide generation and apoptosis. Using a model of ActD-induced apoptosis in mouse embryonic cells, we screened a library of nitroxides to explore structure-activity relationships between their antioxidant/antiapoptotic properties and chemical composition and three-dimensional (3D) structure. High hydrophobicity and effective mitochondrial integration are necessary but not sufficient for high antiapoptotic/antioxidant activity of a nitroxide conjugate. By designing conformationally preorganized peptidyl nitroxide conjugates and characterizing their 3D structure experimentally (circular dichroism and NMR) and theoretically (molecular dynamics), we established that the presence of the beta-turn/beta-sheet secondary structure is essential for the desired activity. Monte Carlo simulations in model lipid membranes confirmed that the conservation of the d-Phe-Pro reverse turn in hemi-GS analogs ensures the specific positioning of the nitroxide moiety at the mitochondrial membrane interface and maximizes their protective effects. These new insights into the structure-activity relationships of nitroxide-peptide and -peptide isostere conjugates are instrumental for development of new mechanism-based therapeutically effective agents.

Animals↗
PubMed2006

Isonitrile trapping reactions under thermolysis of alkoxyamines for the synthesis of quinolines.

[reaction: see text] An efficient tandem radical process comprising a thermal alkoxyamine homolysis, an isonitrile trapping reaction, a 5-exo-trig cyclization, and a homolytic aromatic substitution leads to substituted dihydroquinolines. Depending on the substituent R(1), oxidation to dihydro-1H-cyclopenta[b]quinolines (for R(1) = aryl) or tautomerization to tetrahydro-1H-cyclopenta[b]quinolines (for R(1) = CO(2)Me, CN) occurs. The heterocycles are obtained in moderate to good yields. Upon using microwave-induced heating, the reaction time can be shortened from 3 days to 30 min.

Journal Article↗
PubMed2005

Stereoselective cyclization reactions of IBX-generated alkoxyamidyl radicals.

In this paper, a method for the generation of alkoxyamidyl radicals is presented. These N-centered radicals can efficiently be formed starting from the corresponding acylated alkoxyamines using IBX as an oxidant. Stereoselective 5-exo and 6-exo reactions with these N-heteroatom-centered radicals leading to isoxazolidines and [1,2]oxazinanes are discussed. The N-O bond in the heterocycles can readily be cleaved with SmI(2) to provide N-acylated 1,3-amino alcohols.

Journal Article↗
PubMed2005

Tin-free radical alkoxyamine addition and isomerization reactions by using the persistent radical effect: variation of the alkoxyamine structure.

Various C-centered radicals can efficiently be generated through thermal C-O-bond homolysis of alkoxyamines. This method is used to perform environmentally benign radical cyclization and intermolecular addition reactions. These alkoxyamine isomerizations and intermolecular carboaminoxylations are mediated by the persistent radical effect (PRE). In the paper, the effect of the variation of the alkoxyamine structure--in particular steric effects in the nitroxide moiety--on the outcome of the PRE mediated radical reactions will be discussed. Fourteen different nitroxides were used in the studies. It will be shown that reaction times can be shortened about 100 times upon careful tuning of the alkoxyamine structure. Activation energies for the C-O-bond homolysis of the various alkoxyamines are provided. The kinetic data are used to explain the reaction outcome of the PRE-mediated processes.

Journal Article↗
PubMed2005

Nitroxide-mediated radical processes.

In the present short review article recent achievements in nitroxide-mediated radical polymerizations are presented. The basic concept behind these reactions, which is the Persistent Radical Effect (PRE), will be briefly explained. The effect of the nitroxide structure on the polymerization process will be discussed. Moreover, results of nitroxide-mediated radical polymerizations in aqueous dispersions will be summarized. Finally, applications of the PRE to environmentally benign radical chemistry such as nitroxide-mediated alkoxyamine isomerization and carboaminoxylation reactions are presented. Moreover, the potential use of microwave-induced heating to conduct these thermal radical reactions will be discussed.

Cyclic N-Oxides↗
PubMed2005

Evolution of functional cyclohexadiene-based synthetic reagents: the importance of becoming aromatic.

Suites of new precursors designed around a cyclohexadiene core and intended to mediate "clean" radical chain syntheses have been prepared and tested. 1-Functionalized cyclohexa-2,5-dienes were found to readily donate H-atoms, and the resulting cyclohexadienyl radicals rapidly extruded their functional group as a free radical, because this beta-scission restored aromaticity to the ring. This concept was employed to generate designer radicals from esters of the corresponding alcohols with 1-methyl- or 1-phenylcyclohexa-2,5-diene-1-carboxylic acids. In a similar way, pre-adapted carbamoyl radicals were obtained from cyclohexadienyl-amides and proved advantageous for syntheses of alpha- and beta-lactams. Oxime ether substituted carbamoyl radicals cyclized successfully in convenient syntheses of dihydroindolin-2-ones with N-functionality at the 3-position. Similarly, silicon-centered radicals were obtained from 1-silylated cyclohexadienes, and these reagents proved to be very efficient, environmentally benign organotin hydride substitutes. Radical reactions including reductions, cyclizations, intermolecular additions, and hydrosilylations were carried out in high yields with this reagent. Other heteroatom-centered radicals, especially N-centered radicals, were obtained from appropriate cyclohexadienes enabling chain hydroaminations to be conducted. Several of the cyclohexadiene precursors proved to be useful for electron paramagnetic resonance (EPR) spectroscopic purposes, and this enabled rate constants for fragmentations of the cyclohexadienyl radicals to be obtained. Kinetic data for H-atom abstraction from cyclohexadienes, the second propagation step of the chain processes, was derived from customized radical clocks and from EPR measurements. In this way, conceptual tools were developed for improving future synthetic methodology based around these reagents.

Acids↗
PubMed2004

One-pot homolytic aromatic substitutions/HWE olefinations under microwave conditions for the formation of a small oxindole library.

[reaction: see text] An efficient one-pot sequence comprising a homolytic aromatic substitution followed by an ionic Horner-Wadsworth-Emmons olefination for the preparation of a small library of alpha,beta-unsaturated oxindoles is presented. Microwave-induced heating is used to conduct these reactions. The homolytic aromatic substitution is mediated by the persistent radical effect.

Journal Article↗
PubMed2004

Stereoselective synthesis of (+)-nephrosteranic acid, (+)-trans-cognac lactone, and (+)-trans-whisky lactone using a chiral cyclohexadienyl Ti compound.

We present the stereoselective transfer of cyclohexadienyl from 3-metalated 1,4-cyclohexadienes to various aldehydes. Lewis-acid-mediated "allylation" of aldehydes by treatment with 3-silylated and 3-stannylated 1,4-cyclohexadienes could not be achieved with high diastereoselectivity. In contrast, cyclohexadienyl titanium compounds reacted with both aliphatic and aromatic aldehydes with good-to-excellent diastereoselectivities. Reaction of a chiral TADDOL-derived (TADDOL, 2,2-dimethyl-alpha,alpha,alpha',alpha'-tetraphenyl-1,3-dioxolandimethanol) cyclohexadienyl Ti derivative with various aldehydes led to the corresponding homoallylic alcohols with excellent diastereo- and enantioselectivities. Lower selectivities were obtained with chiral B-cyclohexadienyldiisopinocampheylborane. The 1,3-cyclohexadienes are very useful building blocks for the preparation of biologically important gamma-butyrolactones. Short efficient syntheses of (+)-nephrosteranic acid, (+)-trans-whisky lactone, and (+)-trans-cognac lactone by desymmetrization of 1,4-cyclohexadiene are described.

Aldehydes↗
PubMed2004

Tin-free radical chemistry using the persistent radical effect: alkoxyamine isomerization, addition reactions and polymerizations.

In this tutorial review applications of alkoxyamines as C-radical precursors for the conduction of tin-free radical reactions are presented. These processes are controlled by the Persistent Radical Effect. A brief introduction on the Persistent Radical Effect is provided. In addition, the use of microwave irradiation to conduct thermal radical reactions is discussed. Finally, the use of alkoxyamines as initiators/mediators for the controlled/living radical polymerization is highlighted.

Journal Article↗
PubMed2004

Steric and electronic effects in cyclic alkoxyamines--synthesis and applications as regulators for controlled/living radical polymerization.

The synthesis of new six- and seven-membered cyclic alkoxyamines bearing ethyl groups at the alpha-N position of the alkoxyamines is described. The key step in the synthesis of the sterically hindered six-membered cyclic alkoxyamines is a Wadsworth-Horner-Emmons olefination with bisphosphonate 1. The seven-membered cyclic alkoxyamines were prepared from the corresponding six-membered keto alkoxyamines by ring-enlargement with trimethylsilyl(TMS)-diazomethane. The use of the new alkoxyamines as regulators/initiators for radical polymerization is discussed. Efficient controlled and living polymerization of styrene and n-butyl acrylate was obtained with the six-membered tetraethyl alkoxyamine 13. Controlled polymerizations can be conducted even at 90 degrees C. In addition, alkoxyamine 13 can be used for the preparation of AB diblock and ABA triblock copolymers with narrow polydispersities. The influence of the replacement of methyl groups in the alpha-position of the N atom in cyclic alkoxyamines by larger ethyl groups on the styrene polymerization (reaction time, PDI, kinetics of the C-O bond homolysis) is discussed. In addition, thermal decomposition of the new alkoxyamines was studied. Furthermore, the synthesis of N,N-bissilylated alkoxyamines is described. The silylated alkoxyamines are not suitable as regulators/initiators for the controlled/living radical polymerization. The C-O bonds in silylated alkoxyamines are stronger than the C-O bonds in analogous N,N-dialkylated alkoxyamines. The experimental results are verified by calculations with Gaussian 98 (A. 9).

Journal Article↗
PubMed2003

Hydroxy- and silyloxy-substituted TEMPO derivatives for the living free-radical polymerization of styrene and n-butyl acrylate: synthesis, kinetics, and mechanistic studies.

The synthesis of new 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) styryl derivatives as mediators for the living free-radical polymerization is described. Two of the alpha-methyl groups at the 2- and 6-position of the parent TEMPO styryl alkoxyamine have been replaced by hydroxymethyl and silyloxymethyl groups. To further increase the steric hindrance around the alkoxyamine oxygen atom, the remaining two methyl groups have been substituted with larger ethyl groups. Styrene polymerizations using hydroxy-substituted TEMPO derivatives are fast, but are not well-controlled. As previously shown for other OH-substituted alkoxyamines, intramolecular H-bonding leads to an acceleration of the C-O bond homolysis and, hence, to an acceleration of the polymerization process. However, the OH groups also increase the alkoxyamine decomposition rate constant. The kinetics of the C-O bond homolysis have been determined using EPR spectroscopy. Decomposition studies have been conducted with the aid of 1H NMR spectroscopy. In contrast to the OH-substituted alkoxyamines, highly hindered silyloxy-substituted TEMPO alkoxyamines turned out to be excellent mediator/initiators for the controlled styrene polymerization. Polystyrene with M(n) of up to 80 000 g/mol and narrow polydispersities (PDI) has been prepared using the new alkoxyamines. Reactions have been conducted at 105 degrees C; however, even at 90 degrees C controlled but slow polymerizations can be achieved. Furthermore, and more importantly, poly(n-butyl acrylates) with narrow PDIs (<1.15) have been prepared at 105 degrees C with the new alkoxyamines. Controlled acrylate polymerization can be conducted at temperatures as low as 90 degrees C. The silylated alkoxyamines presented belong to the most efficient initiator/mediators for the controlled acrylate polymerization known to date. The effect of the addition of free nitroxide on the acrylate polymerization is discussed. Moreover, the synthesis of diblock copolymers with narrow PDIs is described.

Journal Article↗
PubMed2003

Intermolecular radical addition and addition/cyclization reactions of alkoxyamines onto nonactivated alkenes.

[reaction: see text] Alkoxyamines A, which are readily prepared from commercially available starting materials, undergo efficient thermal radical carboaminoxylations onto various nonactivated alkenes to provide 1,4-functionalized malonates B in good to excellent yields. The experiments are very easy to conduct. The carboaminoxylations can be combined with radical cyclization and fragmentation processes.

Journal Article↗
PubMed2003

Two types of intramolecular homolytic substitution reactions at group XIV atoms: unusual radical 1,4-Sn shifts from Si to C and carbonylative SHi reaction at Si.

4-[(Trimethylstannyl)diphenylsilyl]butanoyl radical, arising from the corresponding 3-(stannylsilyl)propyl radical and CO, undergoes an SHi reaction at Si with extrusion of trimethyltin radical to give silacyclopentanone. The parent 3-(stannylsilyl)propyl radical was also found to isomerize to (3-stannylpropyl)silyl radical via a 1,4-Sn shift from Si to C with a rate constant of 9.3 x 10(4) s-1 at 80 degrees C. Ab initio and DFT MO calculations support a front-side attack mechanism.

Journal Article↗
PubMed2003

Silylated cyclohexadienes as new radical chain reducing reagents: preparative and mechanistic aspects.

Various silylated 1,4-cyclohexadienes are presented as superior tin hydride substitutes for the conduction of various radical chain reductions. Debrominations, deiodinations, and deselenations can be performed using these environmentally benign reagents. Furthermore, Barton-McCombie-type deoxygenations using silylated cyclohexadienes are described. Radical cyclizations, ring expansions, and Giese-type addition reactions with the new tin hydride substitutes are presented. The polymerization of styrene can be regulated using silylated cyclohexadienes. Rate constants for hydrogen atom abstraction from two 1-silyl-cyclohexadienes by primary C-radicals were determined. The effects of the cyclohexadiene substituents on the reaction outcomes are discussed. Finally, qualitative EPR experiments on silyl radical expulsion from silylated cyclohexadienyl radicals are presented.

Journal Article↗