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PubMedDate not supplied

Oxidation of ABTS by silicate-immobilized cytochrome c in nonaqueous solutions.

Cytochrome c can be readily adsorbed onto mesoporous silicates at high loadings of up to 10 mmol g(-)(1) of silicate. The adsorbed protein retains its peroxidative activity, with no diffusional limitations being observed. The protein can be adsorbed onto the external surface of the silicate or, provided that the pore diameter is sufficiently large, into the channels. In aqueous buffer, the catalytic activity of the adsorbed protein (for the oxidation of ABTS) decreased with increasing temperature, with the decrease being less marked for cytochrome c held within the silicate channels. Similar results were obtained in 95% methanol. Analysis of kinetic data showed that significant increases in k(cat)/K(M) occurred in methanol, ethanol, and formamide, with slight decreases occurring in 1-methoxy-2-propanol. The observed increases were primarily a result of substantial increases in k(cat), while the results in 1-methoxy-2-propanol can be ascribed to increases in K(M). Resonance Raman spectroscopy indicated that the structure of the heme environment of the adsorbed protein was essentially unchanged, in aqueous buffer and in the nonaqueous solvents, methanol, 1-methoxy-2-propanol, and ethanol. In addition, Raman spectra of the lyophilized protein indicated that there were no apparent changes in the heme structure.

Adsorption↗
PubMedDate not supplied

The use of solid-phase supported 1-N-piperazine-4-N-carboxaldehyde in Vilsmeier reactions.

A Vilsmeier salt supported on solid phase was prepared using piperazine bound to Merrifield resin. Piperazine was selected because it contains two secondary amines: one of the amines is protected upon binding to the resin, and the second was formylated to give resin-1-N-piperazine-4-N-carboxaldehyde (9). Activation of the formamide with either bis(trichloromethyl)carbonate (BTC) or POCl(3) afforded the Vilsmeier salt 10. Several olefins were used to test the supported Vilsmeier reagent. The in-solution activation with BTC and POCl(3) of various secondary amides was also evaluated: dimethylformamide (1), N-methyformanilide (4), 4-formylmorpholine (5), and 1,4-dicarboxylpiperazine (6), which showed that amides with one additional heteroatom increase the yields in the Vilsmeier salt formation.

Journal Article↗
PubMed2004

Development and evaluation of microarray-based whole-genome hybridization for detection of microorganisms within the context of environmental applications.

The detection and identification of microorganisms in natural communities is a great challenge to biologists. Microarray-based genomic technology provides a promising high-throughput alternative to traditional microbial characterization. A novel prototype microarray containing whole genomic DNA, termed community genome array (CGA), was constructed and evaluated. Microarray hybridizations at 55 degrees C using 50% formamide permitted the examined bacteria to be distinguished at the species level, while strain-level differentiation was obtained at hybridization temperatures of 65 or 75 degrees C. The detection limit was estimated to be approximately 0.2 ng with genomic DNA from a single pure culture using a reduced hybridization volume (3 microL). Using mixtures of known amounts of DNA or a known number of cells from 14 or 16 different species, respectively, about 5 ng of genomic DNA or 2.5 x 10(5) cells were detected under the hybridization conditions used. In addition, strong linear relationships were observed between hybridization signal intensity and target DNA concentrations for pure cultures, a mixture of DNA templates, and a population of mixed cells (r2 = 0.95-0.98, P < 0.01). Finally, the prototype CGA revealed differences in microbial community composition in soil, river, and marine sediments. The results suggest that CGA hybridization has potential as a specific, sensitive, and quantitative tool for detection and identification of microorganisms in environmental samples.

Bacteria↗
PubMed2003

Solvent-dependent dynamics of the MQ*-->ReII excited-state electron transfer in [Re(MQ+)(CO)3(dmb)]2+.

The Re-->MQ(+) MLCT excited state of [Re(MQ(+))(CO)(3)(dmb)](2+) (MQ(+) = N-methyl-4,4'-bipyridinium, dmb = 4,4'-dimethyl-2,2'-bipyridine), which is populated upon 400-nm irradiation, was characterized by picosecond time-resolved IR and resonance Raman spectroscopy, which indicate large structural differences relative to the ground state. The Re-->MQ(+) MLCT excited state can be formulated as [Re(II)(MQ*)(CO)(3)(dmb)](2+). It decays to the ground state by a MQ*-->Re(II) back-electron transfer, whose time constant is moderately dependent on the molecular nature of the solvent, instead of its bulk parameters: formamides approximately DMSO approximately MeOH (1.2-2.2 ns) < THF, aliphatic nitriles (3.2-3.9 ns) << ethylene-glycol approximately 2-ethoxyethanol (4.2-4.8 ns) < pyridine (5.7 ns) < MeOCH(2)CH(2)OMe (6.9 ns) < PhCN (7.5 ns) < MeNO(2) (8.6 ns) <<< CH(2)Cl(2), ClCH(2)CH(2)Cl (25.9-28.9 ns). An approximate correlation was found between the back-reaction rate constant and the Gutmann donor number. Temperature dependence of the decay rate measured in CH(2)Cl(2), MeOH, and BuCN indicates that the inverted MQ*-->Re(II) back-electron transfer populates a manifold of higher vibrational levels of the ground state. The solvent dependence of the electron transfer rate is explained by solvent effects on inner reorganization energy and on frequencies of electron-accepting vibrations, by interactions between the positively charged MQ(+) pyridinium ring and solvent molecules in the electron-transfer product, that is the [Re(MQ(+))(CO)(3)(dmb)](2+) ground state.

Journal Article↗
PubMed2005

Antitumor metallothiosemicarbazonates: structure and antitumor activity of palladium complex of phenanthrenequinone thiosemicarbazone.

The crystal structure of the potential antitumor metal compound, viz. chloro, mono(phenanthrenequinone thiosemicarbazonato) palladium(II) dimethyl formamide solvate, is reported. The central palladium(II) atom is in a square planar environment provided by the tridentate, monoanionic thiosemicarbazone ligand and the ancillary chloride ion. The compound exhibited remarkable activity against drug-sensitive and drug-resistant breast cancer cell lines and was relatively nontoxic toward the normal mammary epithelial cells. The drug-induced killing effect against breast cancer cell lines was predominantly mediated via apoptosis, a physiologic form of cell death.

Antineoplastic Agents↗
PubMed2005

Synthesis, characterization, crystal structure, and electrochemical, photophysical, and protein-binding properties of luminescent rhenium(I) diimine indole complexes.

We report the synthesis, characterization, and photophysical and electrochemical properties of a series of luminescent rhenium(I) diimine indole complexes, [Re(N-N)(CO)3(L)](CF3SO3) (N-N = 3,4,7,8-tetramethyl-1,10-phenanthroline (Me4-phen), L = N-(3-pyridoyl)tryptamine (py-3-CONHC2H4-indole) (1a), N-[N-(3-pyridoyl)-6-aminohexanoyl]tryptamine, (py-3-CONHC5H10CONHC2H4-indole) (1b); N-N = 1,10-phenanthroline (phen), L = py-3-CONHC2H4-indole (2a), py-3-CONHC5H10CONHC2H4-indole (2b); N-N = 2,9-dimethyl-1,10-phenanthroline (Me2-phen), L = py-3-CONHC2H4-indole (3a), py-3-CONHC5H10CONHC2H4-indole (3b); N-N = 4,7-diphenyl-1,10-phenanthroline (Ph2-phen), L = py-3-CONHC2H4-indole (4a), py-3-CONHC5H10CONHC2H4-indole (4b)), and their indole-free counterparts, [Re(N-N)(CO)3(py-3-CONH-Et)](CF3SO3) (py-3-CONH-Et = N-ethyl-(3-pyridyl)formamide; N-N = Me4-phen (1c), phen (2c), Me2-phen (3c), Ph2-phen (4c)). The X-ray crystal structure of complex 3a has also been investigated. Upon irradiation, most of the complexes exhibited triplet metal-to-ligand charge-transfer (3MLCT) (d pi(Re) --> pi*(diimine)) emission in fluid solutions at 298 K and in low-temperature glass. However, the structural features and long emission lifetimes of the Me4-phen complexes in solutions at room temperature suggest that the excited state of these complexes exhibited substantial triplet intraligand (3IL) (pi --> pi*) (Me4-phen) character. The binding interactions of these complexes to indole-binding proteins including bovine serum albumin and tryptophanase have been examined.

Crystallization↗
PubMed1999

15N NMR and Electrochemical Studies of [Ru(II)(hedta)](-) Complexes of NO, NO(+), NO(2)(-), and NO(-).

[Ru(II)(hedta)L](n)()(-) complexes (hedta(3)(-) = N-(hydroxyethyl)ethylenediaminetriacetate; L = NO(+), n = 0; L = NO, n = 1; L = NO(-), n = 2) have been prepared by the displacement of H(2)O/D(2)O via NO(g) or NO(2)(-). This is the first reported entire set of NO(+), NO, and NO(-) as ligands for the same metal center in a constant oxidation state and with a constant ligand environment (here Ru(II) and the amino carboxylate hedta(3)(-)). From the NO stretching frequencies of isolated salts, the net influence of back-donation by Ru(II) and its sigma-withdrawal was observed to be that the bond order for the NO(+) complex is virtually the same (ca. 2.46) as that for the NO complex (ca. 2.48). The back-donation to NO(-) is also small, as is that to NO, but orbital mixing of NO(-) and Ru(II) is sufficiently important to induce a singlet NO(-) complex. Values for the nu(NO) in cm(-)(1) for the (14)N- and (15)N-labeled complexes, respectively, are as follows: NO(+), 1846, 1827; NO, 1858, 1842; NO(-), 1383, 1370. Combined results of (15)N, (13)C, and (1)H NMR spectra of the complexes in D(2)O show that [Ru(II)(hedta)((15)NO(+))] is a single cis-equatorial isomer with its (15)NO(+) resonance at 249.6 ppm vs [(15)N]formamide. The two-electron-reduced [Ru(II)(hedta)((15)NO(-))](2)(-) complex exists as trans- and cis-equatorial isomers having (15)NO(-) resonances at 609.4 and 607.4 ppm. The (15)N resonances appear at 260.0 ppm for the (15)NO(+) ligand and at 348.8 ppm for the bound (15)NO(2)(-) ligand in the [Ru(II)(hedta)((15)NO(2)(-))((15)NO(+))(D(2)O)] complex. Differential pulse voltammetric waves for the [Ru(II)(hedta)L](n)()(-) series occur at -0.37 V for the Ru(II)(NO(-))/Ru(II)(NO) couple, at -0.10 V for the Ru(II)(NO)/Ru(II)(NO(+)) couple, and at +0.98 V for the Ru(II)(NO(+))/Ru(III)(NO(+)) couple. The coordinated nitrosyl ion/nitro equilibrium (L')Ru(II)(NO(+)) + 2OH(-) right harpoon over left harpoon (L')Ru(II)(NO(2)(-)) + H(2)O (K(NO)()2()-) was observed for L' = hedta(3)(-), as for previous examples with L' = violurate, polypyridyl ligands, and (CN(-))(5) and (NH(3))(5) ligand sets. K(NO)()2()- = 1.44 x 10(13) for L' = hedta(3)(-). log(K(NO)()2()-) is linearly related through the ion-pairing equilibrium constant expression to -z(1)z(2), the charge product of the reacting ions (here the (L')Ru(NO(+)) complex and OH(-)) from -4 through +3, excluding the (NH(3))(m)() ammine series with m = 4 and 5. The opposite behavior of the ammines is attributed to strong solvent H-bonding that changes for reactant and product in the nitrosyl/nitro equilibrium. The pK(a) of coordinated nitrous acid in [Ru(II)(hedta)(HONO)](-) is calculated to be -0.80, a 3.85 log unit enhancement over free HONO due to the Ru(II) charge. An MO explanation is presented to interrelate the {Fe(III)-(NO(-) triplet)} complexes, the {Ru(II)-(NO(-) singlet)} type observed for [Ru(II)(hedta)((15)NO(-))](2)(-), and the NO(+) complexes of other strong-field metals. When both d(z)()()2 and d(x)()()2(-)(y)()()2 metal orbitals reside below the NO pi pair, the electronic repulsions favor a bent NO(-) triplet ligand. If both metal orbitals reside above the NO pi pair, the orbital mixing and back-donation induce a coordinated NO(-) singlet ligand, and if the NO pi pair reside between the two sigma-based d orbitals, an NO(+) ligand and reduced metal center obtain.

Journal Article↗
PubMed2002

Oxo, sulfido, and tellurido Mo-enedithiolate models for xanthine oxidase: understanding the basis of enzyme reactivity.

The active site of the mononuclear molybdenum enzyme xanthine oxidase has an LMoOS(OH) center that catalyzes the hydroxylation of substrate (L representing an enedithiolate ligand contributed by a pterin cofactor in the enzyme). Reaction of the enzyme with cyanide results in the replacement of the Mo=S group with a second Mo=O group, which results in loss of enzyme activity. To understand the basis for this loss of activity, we have computationally examined the interaction of a model for the LMoO2(OH) as well the LMoOTe(OH) congener of the enzyme with formamide (a substrate for the enzyme). Our electronic structure calculations for the oxo congener indicate a reduced electron density on the hydrogen being transferred from substrate in the course of the reaction, a shorter O-H bond in the transition state, and a longer nascent O-C bond of product, factors which combine to account for the loss of reactivity in the LMoO2(OH) species. Interestingly, our calculations indicate that the Te congener is characterized by an increased electron density on the hydrogen species being transferred, a longer Te-H bond in the transition state, and a shorter O-C nascent bond in the product and suggest that a Te congener of xanthine oxidase, were it to be prepared experimentally, should exhibit catalytic activity.

Molecular Mimicry↗
PubMed2002

Mesomorphism, isomerization, and dynamics in a new series of pyramidic liquid crystals.

Nona-alkanoyloxy tribenzocyclononene (CTV-n, where n is the number of carbons in the side chains) were prepared for n = 2 to 14. The homologues of this series appear in two stable isomeric forms, rigid crown and flexible saddle. We report on their isomerization equilibria and dynamics in solution and on their mesomorphic properties in the neat state. The crown-saddle equilibrium and interconversion kinetics of the CTV-8 isomers were studied in dimethyl formamide solutions using high-resolution (1)H NMR in the temperature range from 50 to 130 degrees C. At lower temperatures, the isomerization is too slow to measure. In this range the equilibrium saddle fraction increases from approximately 0.40 to approximately 0.65, whereas the isomerization rate increases from approximately 10(-)(4) to approximately 1 s(-)(1). The saddle isomer undergoes fast pseudorotation at room temperature, but below about -50 degrees C, it becomes slow enough to affect the NMR line width. The rate parameters for this process were estimated from the carbon-13 spectra in methylene chloride solutions to be, k(p)(-100 degrees C) approximately 1.7 x 10(3) s(-)(1) and E(a) approximately 9.6 kJ/mol. The slow crown-saddle isomerization at room temperature (half-life of about one year) allows quantitative separation (by chromatography) of the two isomers and their separate investigation. When the alkanoyloxy side chains are sufficiently long both isomers are mesogenic (n >or= 4 for the saddle and n >or= 5 for the crown), exhibiting hexagonal columnar mesophases. The structure, dynamics, and mesomorphic properties of these mesophase were investigated by X-ray diffraction, optical polarizing microscopy, differential scanning calorimetry, and NMR. The lattice parameters of the crown and saddle mesophases of corresponding homologues are almost identical and increase monotonically with increasing length of the side chains. The clearing temperatures of the saddle isomers are consistently lower than those of the corresponding crowns. Within each series, the clearing temperatures are almost independent of the length of the side chains (156 to 170 degrees C for the crown and 115 to 148 degrees C for the saddle). The thermal and kinetic properties of the neat compounds lead to peculiar phase sequences, as observed in the polarizing microscope and in the DSC thermogram, involving repeated, back and forth, interconversion between the two isomers. Carbon-13 MAS NMR measurements of the crown and saddle mesophases of several homologues were carried out. The spectra of the crown mesophase exhibit dynamic features consistent with planar 3-fold molecular jumps about the column axes. A quantitative analysis for the CTV-8 crown homologue yielded the following Arrhenius parameters, A = 3.1 x 10(22)s(-)(1) and E(a) = 130.1kJ/mol. These unusually high values suggest that the barrier to the jump process is temperature dependent, decreasing with increasing temperature. The rate of this 3-fold jump process is slower for the lower homologues and faster for the higher ones. In contrast, the saddle isomers in the mesophase do not show dynamic effects in their carbon-13 MAS spectra. They do not undergo pseudorotation, and it appears that the molecules remain locked within the columns in a saddle conformation, up to the clearing temperature. However, on (super-)cooling to room temperature and below, selective line broadening is observed in their carbon-13 MAS spectra. This suggests that the saddle conformation is twisted in the mesophase and undergoes fast high-amplitude jumps between the twisted forms. On cooling, these high-amplitude librations freeze out to give an orientationally disordered state. On a very long time scale (of the order of days at 100 degrees C), the saddle mesophase transforms into that of the crown, apparently by sublimation.

Journal Article↗
PubMed2003

Ion solvation thermodynamics from simulation with a polarizable force field.

Thermodynamic measurements of the solvation of salts and electrolytes are relatively straightforward, but it is not possible to separate total solvation free energies into distinct cation and anion contributions without reference to an additional extrathermodynamic assumption. The present work attempts to resolve this difficulty using molecular dynamics simulations with the AMOEBA polarizable force field and perturbation techniques to directly compute absolute solvation free energies for potassium, sodium, and chloride ions in liquid water and formamide. Corresponding calculations are also performed with two widely used nonpolarizable force fields. The simulations with the polarizable force field accurately reproduce in vacuo quantum mechanical results, experimental ion-cluster solvation enthalpies, and experimental solvation free energies for whole salts, while the other force fields do not. The results indicate that calculations with a polarizable force field can capture the thermodynamics of ion solvation and that the solvation free energies of the individual ions differ by several kilocalories from commonly cited values.

Anions↗
PubMed2004

Expanded-size bases in naturally sized DNA: evaluation of steric effects in Watson-Crick pairing.

We describe physicochemical properties in DNA of altered-size nucleobases that retain Watson-Crick analogous hydrogen-bonding ability. Size-expanded analogues of adenine and thymine (xA and xT, respectively, which are expanded by benzo-fusion) were incorporated into natural DNA oligonucleotides, and their effects on helix stability were measured. Base stacking studies revealed that the two stretched analogues stack much more strongly than do their naturally sized counterparts. In contrast to this, pairing studies showed that single substitutions of the new bases are destabilizing to the natural helix as compared to A or T in standard A-T pairs in the same context, unless multiple adjacent substitutions are used. Interestingly, the size-expanded bases displayed selective recognition of the hydrogen-bonding complementary partners, suggesting that Watson-Crick analogous pairs were still formed despite local backbone strain. In an attempt to compensate for the added size of the expanded adenine, we tested a formamide deoxynucleoside, which Leonard proposed as a shortened thymine analogue (F(o)). Data showed, however, that this compound adopts a conformation unfavorable for pairing. On the basis of the combined thermodynamic data, we estimate the energetic cost of the 2.4 A stretching of an isolated base pair in DNA at ca. +1 to 2 kcal/mol. Notably, during the pairing studies, the two size-expanded nucleobases were found to display significant changes in fluorescence on formation of stacked versus unstacked structures, suggesting possible applications in probing nucleic acid structures and biochemical mechanisms.

Base Pairing↗
PubMed2006

Aryl transfer between Pd(II) centers or Pd(IV) intermediates in Pd-catalyzed domino reactions.

A computational study has been performed to determine the mechanism of the key steps of Pd-catalyzed domino reactions in which C(sp2)-C(sp2) are formed from aryl and alkenyl halides. DFT calculations were done on model complexes of the proposed intermediates, with PH3 and H2O as ancillary ligands, to explore two possible mechanisms: the oxidative addition of aryl or alkenyl halides to palladacycles to give Pd(IV) intermediates, and the transmetalation-type reaction of aryl or alkenyl ligands between two Pd(II) centers, a palladacycle, and a Pd(II) complex formed by oxidative addition of aryl or alkenyl halides to Pd0. We have shown that oxidative addition of iodoethylene to Pd0 precursors is more favorable than oxidative addition to Pd(II) palladacycles, whereas transmetalation-type reactions between Pd(II) complexes are facile. Similar results were obtained with iodobenzene instead of iodoethylene and formamide as the ancillary ligand. These results suggest that Pd(IV) intermediates are not involved in these reactions.

Journal Article↗
PubMed2006

Synthesis, anion exchange, and delamination of Co-Al layered double hydroxide: assembly of the exfoliated nanosheet/polyanion composite films and magneto-optical studies.

This paper describes a systematic study on the synthesis, anion exchange, and delamination of Co-Al layered double hydroxide (LDH), with the aim of achieving fabrication and clarifying the properties of LDH nanosheet/polyanion composite films. Co-Al-CO3 LDH hexagonal platelets of 4 mum in lateral size were synthesized by the urea method under optimized reaction conditions. The as-prepared CO3(2-)-LDH was converted to Cl- -LDH by treating with a NaCl-HCl mixed solution, retaining its high crystallinity and hexagonal platelike morphology. LDHs intercalated with a variety of anions (such as NO3-, ClO4-, acetate, lactate, dodecyl sulfate, and oleate) were further prepared from Cl- -LDH via an anion-exchange process employing corresponding salts. Exchanged products in various anion forms were found to show different delamination behaviors in formamide. Among them, best results were observed for NO3- -LDH in terms of the exfoliating degree and the quality of the exfoliated nanosheets. The delamination gave a pink transparent suspension containing well-defined nanosheets with lateral sizes of up to 2 microm. The resulting nanosheets were assembled layer-by-layer with an anionic polymer, poly(sodium styrene 4-sulfonate) (PSS), onto quartz glass substrates to produce composite films. Magnetic circular dichroism (MCD) measurements revealed that the assembled multilayer films exhibited an interesting magneto-optical response.

Journal Article↗
PubMed2006

Free-radical version of the strecker synthesis of alpha-aminoamides promoted by aqueous H2O2/TiCl3/HCONH2 system.

A new reaction of general synthetic interest representing the free-radical version of the Strecker synthesis to alpha-aminoamides is reported. A hydroxy radical, generated by Ti(III) one-electron reduction of H2O2, abstracts a H atom from the C-H bond of formamide, and the resulting carbamoyl radical adds to the C atom of aldimines formed in situ, leading to a one-pot synthesis of alpha-aminoamides. Several types of aldehydes can participate in this process.

Journal Article↗
PubMed2006

Synthesis, DNA polymerase incorporation, and enzymatic phosphate hydrolysis of formamidopyrimidine nucleoside triphosphates.

The nucleoside triphosphates of N6-(2-deoxy-alpha,beta-d-erythro-pentofuranosyl)-2,6-diamino-4-hydroxy-5-formamidopyrimidine (Fapy.dGTP) and its C-nucleoside analogue (beta-C-Fapy.dGTP) were synthesized. The lability of the formamide group required that nucleoside triphosphate formation be carried out using an umpolung strategy in which pyrophosphate was activated toward nucleophilic attack. The Klenow fragment of DNA polymerase I from Escherichia coli accepted Fapy.dGTP and beta-C-Fapy.dGTP as substrates much less efficiently than it did dGTP. Subsequent extension of a primer containing either modified nucleotide was less affected compared to when the native nucleotide is present at the 3'-terminus. The specificity constants are sufficiently large that nucleoside triphosphate incorporation could account for the level of Fapy.dG observed in cells if 1% of the dGTP pool is converted to Fapy.dGTP. Similarly, polymerase-mediated introduction of beta-C-Fapy.dG could be useful for incorporating useful amounts of this nonhydrolyzable analogue for use as an inhibitor of base excision repair. The kinetic viability of these processes is enhanced by inefficient hydrolysis of Fapy.dGTP and beta-C-Fapy.dGTP by MutT, the E. coli enzyme that releases pyrophosphate and the corresponding nucleoside monophosphate upon reaction with structurally related nucleoside triphosphates.

Base Sequence↗
PubMed2002

3-deoxypentosulose: an alpha-dicarbonyl compound predominating in nonenzymatic browning of oligosaccharides in aqueous solution.

The thermal degradation of D-glucose, maltose, and maltotriose in aqueous solution was investigated under caramelization (no glycine) and Maillard (with glycine) conditions. Degradation of the sugar and alpha-dicarbonyls product was monitored. Under both caramelization and Maillard reaction conditions, 3-deoxypentosulose was the predominating alpha-dicarbonyl compound formed from maltose and maltotriose. In the absence of an amino compound, however, 3-deoxypentosulose is formed in much lower concentration. It was concluded that 3-deoxypentosulose is formed by a pathway specific for oligo- and polysaccharides since this alpha-dicarbonyl is formed from the alpha-1-->4 glucans such as maltose and maltotriose but not from glucose. For its formation, a retro Claisen reaction of an enolization product of 1-amino-1,4-dideoxyhexosulose is proposed as the route to its formation. 1-Amino-1,4-dideoxyhexosulose could be formed by vinylogous alpha-elimination from the 2,3-enediol structure after Amadori rearrangement, favored by planar alignment of the bonds between C1 and C4. Subsequent rearrangement by keto-enoltautomerization leads to a 1-imino-3-keto structure. In this structure, attack of a hydroxyl anion, provided by water at neutral pH, could cause a splitting off of the C1. This reaction gives rise to formic acid or formamide and a pentose derivative, which reacts further to give 3-deoxypentosulose.

Glucose↗
PubMed1995

Synthesis and in vitro activity of 17 beta-(N-alkyl/arylformamido)- and 17 beta-[(N-alkyl/aryl)alkyl/arylamido]-4-methyl-4-aza-3-oxo-5 alpha-androstan-3-ones as inhibitors of human 5 alpha-reductases and antagonists of the androgen receptor.

A number of 17 beta-(N-alkyl/arylformamido)- and 17 beta-[(N-alkyl/aryl)alkyl/arylamido]-3-oxo-4-aza-5 alpha-steroids were prepared from 17 beta-hydroxy-4-azasteroids and evaluated as inhibitors of human 5 alpha-reductase and antagonists of the androgen receptor. Jones' oxidation of 17 beta-hydroxy compounds gave the 17-keto-4-azasteroids, which were treated with amines and NaBH(OAc)3/NaBH3CN to give 17 beta-(N-alkyl/arylamino)-4-azasteroids 10-27. Alternatively, the above-indicated compounds were prepared from amines and 17-keto-4-azasteroids to form imines, which were then reduced with NaBH4. Formylation of amines 10-27 gave 17 beta-(N-alkylformamides) 28-41; however, acylation afforded 17 beta-[(N-alkyl/aryl)alkyl/arylamides] 42-53. In comparison to N,N-diethyl-4-methyl-3-oxo-4-aza-5 alpha-androstane-17 beta-carboxamide (4-MA; IC50 = 4.15 nM), 17 beta-(N-alkylformamido)-4-azasteroids were potent inhibitors of human type I 5 alpha-reductase, IC50 values of compounds 29, 30, 36, and 37 being measured as 3.05, 0.91, 2.19, and 2.35 nM, respectively. The structure-activity relationships suggest that the type I enzyme has preference for N-substituted straight alkyl side chains of four to five carbon atoms. On the other hand, formamides 32 (N-heptyl) and 33 (N-octyl), in addition to inhibiting the type I enzyme (IC50s = 9.57 and 16.9 nM, respectively), showed also strong inhibitory activity (IC50s = 14.0 and 18.4 nM, respectively) for human type II 5 alpha-reductase, in comparison to N-(1',1'-dimethylethyl)-3-oxo-4-aza-5 alpha-androst-1-ene-17 beta-carboxamide (MK-906; IC50 = 4.53 nM). Other compounds in this series showed moderate activities (IC50 > 100 nM) on the type II enzyme. 17 beta-[(N-Alkyl/aryl)alkyl/arylamides] 45, 46, 48, and 51 exhibited highly potent inhibitory activity for human type I 5 alpha-reductase with IC50s of 1.77, 2.42, 2.93, and 5.44 nM, respectively, while moderate to no effect was observed on the type II enzyme (100 < IC50s < 1000 nM), except for compound 48 (IC50 = 3.75 nM). In another substitution pattern, N-aryl/alkylamides were studied; an electron-donating group increased the potency of compound 51, whereas an electron-withdrawing group decreased the potency of compounds 52 and 53 compared to parent compound 50. In addition to their 5 alpha-reductase activities, 17 beta-(N-alkylformamides) were also studied for their inhibitory activities on dihydrotestosterone (DHT)-stimulated proliferation of androgen-sensitive Shionogi mouse mammary carcinoma cells (clone SEM-107).(ABSTRACT TRUNCATED AT 400 WORDS)

Androgen Receptor Antagonists↗
PubMed1994

Nonpeptidic inhibitors of human leukocyte elastase. 3. Design, synthesis, X-ray crystallographic analysis, and structure-activity relationships for a series of orally active 3-amino-6-phenylpyridin-2-one trifluoromethyl ketones.

A series of nonpeptidic inhibitors of human leukocyte elastase (HLE) is reported. These trifluoromethyl ketone-based inhibitors contain a 3-amino-6-phenylpyridone group as a central template. The effect of varying the N-3 substituent in these inhibitors on in vitro potency, physical properties, and oral activity in a hamster based, HLE-induced lung damage model is described. The variety of substituents at this position that have little effect on in vitro potency supports the idea that this region of the molecule does not interact strongly with the enzyme. One exception to this generality is 13k, which is substituted with a (4-acetamidophenyl)sulfonyl group. This compound has a K(i) of 0.7 nM and is, in vitro, the most potent inhibitor in the series. In contrast, variation of the N-3 substituent was found to have a dramatic effect on activity after oral administration. Several analogs, including the parent amine, 7, formamide, 2u, benzyl sulfamide, 13e, and benzyl sulfonamide, 13f, show significant activity when administered at an oral dose of 2.5 mg/kg. Support for the modeling-based design concepts was obtained through in vitro SAR results and X-ray crystallographic analysis of the complex between 13d and porcine pancreatic elastase (PPE), a closely related enzyme.

Acetamides↗