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Biomedical subjects

Ronald Breslow

Publications and source records attributed to Ronald Breslow.

At least 19 recordsLinked to original sources
PubMed2007

Dimethyl sulfoxide to vorinostat: development of this histone deacetylase inhibitor as an anticancer drug.

In our quest to understand why dimethyl sulfoxide (DMSO) can cause growth arrest and terminal differentiation of transformed cells, we followed a path that led us to discover suberoylanilide hydroxamic acid (SAHA; vorinostat (Zolinza)), which is a histone deacetylase inhibitor. SAHA reacts with and blocks the catalytic site of these enzymes. Extensive structure-activity studies were done along the path from DMSO to SAHA. SAHA can cause growth arrest and death of a broad variety of transformed cells both in vitro and in tumor-bearing animals at concentrations not toxic to normal cells. SAHA has many protein targets whose structure and function are altered by acetylation, including chromatin-associated histones, nonhistone gene transcription factors and proteins involved in regulation of cell proliferation, migration and death. In clinical trials, SAHA has shown significant anticancer activity against both hematologic and solid tumors at doses well tolerated by patients. A new drug application was approved by the US Food and Drug Administration for vorinostat for treatment of cutaneous T-cell lymphoma. More potent analogs of SAHA have shown unacceptable toxicity.

Animals↗
PubMed2006

Amplification of enantiomeric concentrations under credible prebiotic conditions.

Solutions with as little as 1% enantiomeric excess (ee) of D- or L-phenylalanine are amplified to 90% ee (a 95/5 ratio) by two successive evaporations to precipitate the racemate. Such a process on the prebiotic earth could lead to a mechanism by which meteoritic chiral alpha-alkyl amino acids could form solutions with high ee values that were needed for the beginning of biology.

Chemical Precipitation↗
PubMed2006

Covalently bridging gaps in single-walled carbon nanotubes with conducting molecules.

Molecular electronics is often limited by the poorly defined nature of the contact between the molecules and the metal surface. We describe a method to wire molecules into gaps in single-walled carbon nanotubes (SWNTs). Precise oxidative cutting of a SWNT produces carboxylic acid-terminated electrodes separated by gaps of </=10 nanometers. These point contacts react with molecules derivatized with amines to form molecular bridges held in place by amide linkages. These chemical contacts are robust and allow a wide variety of molecules to be tested electrically. In addition to testing molecular wires, we show how to install functionality in the molecular backbone that allows the conductance of the single-molecule bridges to switch with pH.

Journal Article↗
PubMed2006

An 11 nm molecular wire that switches electrochemically between an insulating and a fully conjugated conducting state.

[structure: see text] Molecular wires consisting of oligothiophenes and oligothiophenylethynes, ranging in length from 2 to 11 nm, are synthesized and examined by spectroscopy and electrochemistry. UV spectroscopy shows that the longest wires are not fully conjugated, but twisted. However, cyclic voltammetry indicates that their monocations are now flattened and conjugated over the entire length range. In appropriate systems, the wires will link to two electrodes across a nanoscale gap and conduct current.

Journal Article↗
PubMed2006

Metal coordination-directed hydroxylation of steroids with a novel artificial P-450 catalyst.

[structure: see text] A novel catalyst has been synthesized in which a manganese-porphyrin unit is linked to two 2,2'-bipyridyl groups and two pentafluorophenyl groups in trans fashion on its four meso positions. Relative to a previous catalyst in which the manganese-porphyrin had four 2,2'-bipyridyl groups, the new catalyst, in the presence of Cu(2+) ions as coordinating linkers, catalyzes the oxidation of a steroid substrate with much better regioselectivity and higher turnover numbers.

2,2'-Dipyridyl↗
PubMed2005

Hydrophobic and electronic factors in the design of dialkylglycine decarboxylase mimics.

The first functional catalytic mimic of the enzyme dialkylglycine decarboxylase is described. This system utilizes a hydrophobically modified polyethylenimine polymer, a pyridoxamine cofactor, and a 2-aryl-2-alkylglycine sacrificial amine source to convert alpha-keto acids to alpha-amino acids at biologically relevant temperatures with multiple turnovers of the pyridoxamine catalyst. The effects of hydrophobic and electronic factors in the 2,2-disubstituted sacrificial amine source and the pyridoxamine catalyst on turnover frequency and turnover number are explored.

Catalysis↗
PubMed2005

A thiolate ligand on a cytochrome P-450 mimic permits the use of simple environmentally benign oxidants for biomimetic steroid hydroxylation in water.

Manganese porphyrin systems carrying cyclodextrin binding groups can regioselectively and stereoselectively hydroxylate bound steroid substrates, using iodosobenzene as oxidant, but hydrogen peroxide and other simple oxidants such as sodium hypochlorite are not effective in water. Thiol ligands were then added to the catalyst, both covalently attached and hydrophobically bound, and with these ligands hydrogen peroxide was now an effective oxidant.

Cytochrome P-450 Enzyme System↗
PubMed2005

Oxaziridinium salts as hydrophobic epoxidation reagents: remarkable hydrophobically-directed selectivity in olefin epoxidation.

Selective epoxidation of cinnamates versus crotonate was used to detect hydrophobic binding of the cinnamates in the transition states with hydrophobic oxidizing agents in water solution. With peracids as oxidants, no such effect was seen, in accord with the calculated geometries of epoxidation in which the hydrophobic groups of substrate and oxidant could not stack. However, with oxaziridinium salts carrying fused benzene rings there was significantly high selectivity for the cinnamates in water solution, which could be suppressed with added 2-propanol. The hydrophobically induced selectivity changes were even larger, in free energy terms, than those reported previously for the atom-transfer reactions in hydride reductions. Furthermore, the oxaziridinium ions could be generated with oxone from catalytic amounts of the corresponding iminium salts. These substrate selectivities should also carry over to positional selectivities in polyenes.

Alkenes↗
PubMed2005

Chiral polyamines from reduction of polypeptides: asymmetric pyridoxamine-mediated transaminations.

BH3.THF can reduce polypeptides to polyamines with retention of chirality. The resulting polyamines are intriguing general platforms for asymmetric catalysis, given the diverse structures available and their relative ease of synthesis. We have constructed a number of chiral pyridoxamine catalysts based on reduced peptides. These compounds transaminate alpha-ketoacids with moderate to good enantioselectivity, while their peptidyl counterparts show almost no chiral induction.

Boranes↗
PubMed2004

Requirements for selective hydrophobic acceleration in the reduction of ketones.

Reductions of various quaternized hydrophobic beta-keto amines were performed in water and in methanol using borohydride anions carrying hydrophobic groups. The most important requirement of the substrate to permit hydrophobically accelerated selective reductions is the ability of the hydrophobic group of the substrate and its attached keto group to attain a coplanar relationship. Some derivatives of naturally occurring steroid diones have also been employed as substrates to probe the mechanism and utility of these hydrophobically accelerated selective reductions further.

Ketones↗
PubMed2004

Oligothiophene isocyanides for platinum-based molecular electronic applications.

Understanding molecular orientation on a metal surface is key to designing molecular electronic device junctions. Though platinum device electrodes are of particular interest as a more stable alternative to the often used gold electrodes, the chemisorption of conducting molecules onto platinum surfaces has not been thoroughly studied. We present herein the first detailed study of the ability and manner in which soluble oligothiophene isocyanides, of lengths ranging from 2 to 7 nm, chemisorb onto platinum surfaces and nanoparticles. It was found that these oligothiophene isocyanides stand at a 41 degrees angle from the platinum surface normal, suggesting their applicability in molecule-bridged platinum electrode devices.

Journal Article↗
PubMed2004

Transamination reactions with multiple turnovers catalyzed by hydrophobic pyridoxamine cofactors in the presence of polyethylenimine polymers.

Pyridoxamines carrying hydrophobic side chains reversibly bind into the hydrophobic core of polyethylenimines and transaminate ketoacids to amino acids with as much as a 725000-fold rate acceleration. Turnover catalysis was achieved by sacrificial oxidative decarboxylation of C-substituted amino acids, which reconverted the pyridoxals to pyridoxamines.

Hydrophobic and Hydrophilic Interactions↗
PubMed2004

Polymeric and dendrimeric pyridoxal enzyme mimics.

Pyridoxal was covalently attached to polyethylenimine polymers, but the resulting materials were found to degrade rapidly. In comparison, the dendrimeric pyridoxals, which possess only one pyridoxal unit at the core of every dendrimer molecule were found to be relatively stable compounds. A total of 12 poly(amidoamine) type dendrimers were synthesized. They range from G1 to G6 with either NMe(2) or NHAc termini. The NMe(2)-terminated pyridoxal dendrimers racemize alpha-amino acids 50-100 times faster than does simple pyridoxal, while the NHAc-terminated pyridoxal dendrimers racemize alpha-amino acids only 3-5 times faster than does simple pyridoxal. Both the NMe(2)- and NHAc-terminated pyridoxal dendrimers decarboxylate 2-amino-2-phenyl-propionic acid 1-3 times faster than simple pyridoxal. The interior polarity in the pyridoxal dendrimers is similar to that of 85:15 water-DMF solution. Furthermore, we successfully incorporated eight lauryl groups to the G5 pyridoxal dendrimer at known positions. The laurylated dendrimer exhibits lower racemization and decarboxylation rates than do the unlaurylated ones, in contrast to the positive rate effects of laurylation in polyethylenimine-pyridoxamines in our previous transamination studies.

Amino Acids↗
PubMed2004

Determining the geometries of transition States by use of antihydrophobic additives in water.

The quantitative effect of cosolvents on the water solubility of hydrophobic substrates can be correlated with the effect on reaction rates to determine the geometries of transition states for Diels-Alder reactions, the benzoin condensation, and alkylations of phenoxide ions and aniline. Some of these reactions have transition states with packing of hydrophobic surfaces and some do not. Methods were devised to sort out the effect of the cosolvents on solvation of hydrophobic surfaces and the effect on solvation of polar groups. The result is a set of geometries for these reactions that is consistent with theory.

Alcohols↗
PubMed2003

Hydrophobically directed selective reduction of ketones.

Three hydrophobic borohydrides carrying phenyl, pentafluorophenyl, and beta-naphthyl groups were used to reduce ketones in water and in methanol. With ketones carrying phenyl, naphthyl, or biphenyl substituents, there was preferential reduction in methanol of competing acetyl groups, either intermolecular or intramolecular, but preferential reduction of the aryl ketones in water. In the most extreme case, there was a 40-fold selectivity reversal. Lithium borohydride showed no such change in selectivity and favored acetyl reduction in both solvents. Salt and cosolvent effects indicate that hydrophobic packing is involved in the reaction of hydrophobic reagents with the aryl ketones. Some special interaction of the pentafluorophenyl group with aryl rings was also detected.

Benzoates↗
PubMed2003

Dendrimeric pyridoxamine enzyme mimics.

PAMAM dendrimers from generations 1-6 were synthesized with pyridoxamine in their core. They transaminated pyruvic and phenylpyruvic acids in water to alanine and phenylalanine, respectively, with Michaelis-Menten kinetics and high effectiveness compared with simple pyridoxamine. The largest dendrimers-similar in size to some globular proteins-were comparable in effectiveness to a previous polyethylenimine (PEI)-pyridoxamine catalyst, and to a protein-pyridoxamine catalyst, but not as effective as a previous PEI-pyridoxamine carrying lauryl hydrophobic groups. The new catalysts showed both general acid/base catalysis by their amino groups and hydrophobic binding of the phenylpyruvate substrate.

Biomimetic Materials↗
PubMed2003

A forbidden rearrangement.

[reaction: see text] A barrelene derivative fragments to afford benzene and trappable 1,2,3-tricyanocyclopropene. The barrelene anion fragments more easily to liberate benzene and the 1,2,3-tricyanocyclopropenyl anion, which is not trappable or stable in solution. However, the major thermal product from the barrelene anion is a rearranged allyl anion that is formed by disrotatory cleavage of the cyclopropyl ring, a formally Woodward-Hoffmann-forbidden process. Several proposals are offered to rationalize this forbidden rearrangement.

Journal Article↗