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PubMed2005

Optochemical sensor for determining ozone based on novel soluble indigo dyes immobilised in a highly permeable polymeric film.

An optochemical ozone sensor is described that has been manufactured by immobilisation of novel soluble indigo derivatives in permeable transparent polymeric films of polydimethylsiloxane-polycarbonate copolymer. From a number of investigated indigo derivatives, 4,4',7,7'-tetraalkoxyindigo 9 has been selected for optimal sensitivity and specificity of ozone detection. A linear calibration for ozone can be obtained in the range between 0.01 and 0.5 ppm. The limit of quantitation is 0.03 ppm, and the accuracy exceeds 8%. It takes about 134 s to measure the relatively low occupational exposure concentration of 0.1 ppm. A reduction of the sensor response time could be achieved through application of double-sided coated sensors instead of single-sided variants. The stability of the sensors and the effect of external parameters like relative humidity (RH), temperature and gas flow on the sensor response have been investigated. The sensor response is affected by varying the gas flow or temperature; however, humidity in the range between 0 and 90% RH does not affect sensor response. The indigo derivative 9 remained stable inside the polymeric film and no chemical reaction, crystallisation or leaching occurred during 10 months of observation. Proper choice of indicator dye and polymeric material and successful application of kinetic evaluation method for the exposure experiments determine the desired features of the sensor.

Air Pollutants↗

PubMed2000

Consequences of cAMP and catalytic-subunit binding on the flexibility of the A-kinase regulatory subunit.

A combination of site-directed labeling and time-resolved fluorescence anisotropy was used to further elucidate the structure and underlying dynamic features of the type I regulatory (R(I)(alpha)) subunit of the cAMP-dependent protein kinase. Specifically, the consequences of cAMP and the catalytic (C)-subunit binding on the backbone flexibility around seven sites of cysteine substitution and fluorescein maleimide labeling (Thr(6)Cys, Leu(66)Cys, Ser(75)Cys, Ser(81)Cys, Ser(99)Cys, Ser(145)Cys, and Ser(373)Cys) in the R(I)(alpha) subunit were assessed. Focusing on the fast rotational correlation time, the results indicate that most of the interdomain segment connecting the dimerization/docking (D/D) and tandem cAMP-binding domains is probably weakly associated with the latter domain. Also, this segment becomes more tightly bound to the C subunit upon holoenzyme formation. The results also suggest that there is a short 'hinge' segment (around Leu(66)Cys) that could allow the structured interdomain/cAMP-binding and D/D domains to pivot about each other. Finally, cAMP binding dramatically reduces the backbone flexibility around only the two sites of cysteine substitution in the cAMP-binding domains, suggesting a selective structural stabilization caused by cAMP and a "tight" coupling of low-nanosecond fluctuations selectively within the tandem cAMP-binding domains.

Catalysis↗

PubMed1998

Synthesis and characterization of more potent analogues of hirudin fragment 1-47 containing non-natural amino acids.

Hirudin is the most potent and specific inhibitor of thrombin, a key enzyme in the coagulation process existing in equilibrium between its procoagulant (fast) and anticoagulant (slow) form. In a previous study, we described the solid-phase synthesis of a Trp3 analogue of fragment 1-47 of hirudin HM2, which displayed approximately 5-fold higher thrombin inhibitory potency relative to that of the natural product [De Filippis, V., et al. (1995) Biochemistry 34, 9552-9564]. By combining automated and manual peptide synthesis, here we have produced in high yields seven analogues of fragment 1-47 containing natural and non-natural amino acids. In particular, we have replaced Val1 with tert-butylglycine (tBug), Ser2 with Arg, and Tyr3 with Phe, cyclohexylalanine (Cha), Trp, alpha-naphthylalanine (alphaNal), and beta-naphthylalanine (betaNal). The crude reduced peptides are able to fold almost quantitatively into the disulfide-cross-linked species, whose unique alignment (Cys6-Cys14, Cys16-Cys28, and Cys22-Cys37) has been shown to be identical to that of the natural fragment. The results of conformational characterization provide evidence that synthetic peptides retain the structural features of the natural species, whereas thrombin inhibition data indicate that the synthetic analogues are all more potent inhibitors of thrombin. In particular, Val --> tBug exchange leads to a 3-fold increase in binding, interpreted as arising from a favorable reduction of the entropy of binding, due to the presence of the more symmetric side chain of tBug relative to that of Val. The S2R analogue binds 24- and 125-fold more tightly than the natural fragment to the fast or slow form of thrombin. These results are explained by considering that Arg2 may favorably couple to Glu192, a key residue involved in the slow to fast transition, thus stabilizing the slow form. Replacement of Tyr3 with more hydrophobic residues having different side chain orientations and electronic structures improves binding by 2-40-fold, suggesting that nonpolar interactions and shape-dependent packing effects strongly influence binding at this position. Overall, these results provide new insights for elucidating the mechanism of hirudin-thrombin recognition at the molecular level and highlight new strategies for designing more potent and selective inhibitors of thrombin.

Alanine↗

PubMed1997

Mechanism-based phage display selection of active-site mutants of human glutathione transferase A1-1 catalyzing SNAr reactions.

A library of active-site mutants has been constructed by targeting selected amino acid residues in human glutathione transferase (GST) A1-1 for random mutagenesis. The mutated residues are suitably positioned for interaction with the second, electrophilic substrate, in particular chloronitrobenzene derivatives undergoing SNAr reactions. DNA representing the GST A1-1 mutant library was fused with DNA encoding gene III protein, a component of the coat of filamentous phage. Phage display was used for affinity selection of GST A1-1 mutants with altered catalytic properties. The affinity ligand used was the sigma-complex of 1,3,5-trinitrobenzene and glutathione immobilized to Sepharose. The complex was designed to mimic the transition state of SNAr reactions catalyzed by GSTs. The selection system is based on the combination of affinity for the sigma-complex as well as the ability to promote its formation, thus mimicking two salient features of the assumed catalytic mechanism for the SNAr reactions. Many of the GST A1-1 mutants selected and analyzed contained an aromatic amino acid residue in one of the mutated positions, suggesting favorable interactions with the trinitrocyclohexadienate moiety of the affinity ligand. A mutant C36 was selected for more detailed studies. Its catalytic efficiency with several chloronitrobenzene substrates was 20-90-fold lower than that of wild-type GST A1-1, but fully comparable to naturally evolved GSTs of different classes, providing a 10(5)-fold rate enhancement over the uncatalyzed reaction. In the conjugation of ethacrynic acid, a Michael addition reaction, mutant C36 was 13-fold more efficient than the wild-type enzyme. Within experimental error, the quotient between the KF values for wild-type GST A1-1 and mutant C36 is the same as that between the kcat/KM values determined with 1-chloro-2,4-dinitrobenzene for the two enzyme forms. This result indicates that sigma-complex formation is rate-limiting for the catalyzed reaction. Thus, the principle of transition-state stabilization as a component of catalysis has been successfully exploited in affinity selection of catalytically competent GST A1-1 mutants. This mechanism-based procedure also selects for the ability to promote sigma-complex formation, and serves as a probe of the catalytic mechanism.

Bacteriophages↗

PubMed2005

CAGER: classification analysis of gene expression regulation using multiple information sources.

BACKGROUND: Many classification approaches have been applied to analyzing transcriptional regulation of gene expressions. These methods build models that can explain a gene's expression level from the regulatory elements (features) on its promoter sequence. Different types of features, such as experimentally verified binding motifs, motifs discovered by computer programs, or transcription factor binding data measured with Chromatin Immunoprecipitation (ChIP) assays, have been used towards this goal. Each type of features has been shown successful in modeling gene transcriptional regulation under certain conditions. However, no comparison has been made to evaluate the relative merit of these features. Furthermore, most publicly available classification tools were not designed specifically for modeling transcriptional regulation, and do not allow the user to combine different types of features. RESULTS: In this study, we use a specific classification method, decision trees, to model transcriptional regulation in yeast with features based on predefined motifs, automatically identified motifs, ChlP-chip data, or their combinations. We compare the accuracies and stability of these models, and analyze their capabilities in identifying functionally related genes. Furthermore, we design and implement a user-friendly web server called CAGER (Classification Analysis of Gene Expression Regulation) that integrates several software components for automated analysis of transcriptional regulation using decision trees. Finally, we use CAGER to study the transcriptional regulation of Arabidopsis genes in response to abscisic acid, and report some interesting new results. CONCLUSION: Models built with ChlP-chip data suffer from low accuracies when the condition under which gene expressions are measured is significantly different from the condition under which the ChIP experiment is conducted. Models built with automatically identified motifs can sometimes discover new features, but their modeling accuracies may have been over-estimated in previous studies. Furthermore, models built with automatically identified motifs are not stable with respect to noises. A combination of ChlP-chip data and predefined motifs can substantially improve modeling accuracies, and is effective in identifying true regulons. The CAGER web server, which is freely available at http://cic.cs.wustl.edu/CAGER/, allows the user to select combinations of different feature types for building decision trees, and interact with the models graphically. We believe that it will be a useful tool to facilitate the discovery of gene transcriptional regulatory networks.

Algorithms↗

PubMed1996

Structural and quantum chemical factors affecting mutagenic potency of aminoimidazo-azaarenes.

A set of 16 mutagenic aminoimidazo-azaarenes, including four that have been isolated from cooked foods and identified as bacterial mutagens and rodent carcinogens, was selected from a larger series previously published [Hatch et al. (1991): Environ Mol Mutagen 17:4-19] for an in-depth structure-activity study using computational methods. Structural features believed to affect mutagenic potency were tabulated. Molecular orbital energies and other electronic properties of these compounds were calculated using Huckel, semiempirical AM1, and ab initio quantum mechanical methods. Factor interrelationships were studied by multiple linear regression and canonical correlation analyses. Our goal was an improved understanding of the chemical basis of mutagenicity for this class of heterocyclic amines. The major findings were as follows: 1) mutagenic potency is related to the size of the aromatic ring system; 2) potency is enhanced by the presence and location of an N-methyl group; 3) potency is enhanced by addition of ring nitrogen atoms in pyridine, quinoline, and quinoxaline configurations; 4) potency is inversely related to the energy of the LUMO (lowest unoccupied molecular orbital) of the parent amines; 5) potency is directly, though weakly, related to the LUMO energy of the derived nitrenium ions; and 6) the calculated thermodynamic stability of the nitrenium ions (relative to the parent amine) is directly correlated with nitrenium LUMO energy and with the negative charge on the exocyclic nitrogen atom. Although this study raises several intriguing issues relating mutagenicity to chemical properties, further study will be required to determine the plausibility of the nitrenium ion as the ultimate mutagen for binding to DNA.

Benzimidazoles↗

PubMed2005

Evolution of the electronic structure of Be clusters.

Using a modified symbiotic genetic algorithm approach and many-body interatomic potential derived from first principles, we have calculated equilibrium geometries and binding energies of the ground-state and low-lying isomers of Be clusters containing up to 41 atoms. Molecular-dynamics study was also carried out to study the frequency of occurrence of the various geometrical isomers as these clusters are annealed during the simulation process. For a selected group of these clusters, higher-energy isomers were more often found than their ground-state structures due to large catchment areas. The accuracy of the above ground-state geometries and their corresponding binding energies were verified by carrying out separate ab initio calculations based on molecular-orbital approach and density-functional theory with generalized gradient approximation for exchange and correlation. The atomic orbitals were represented by a Gaussian 6-311G** basis, and the geometry optimization was carried out using the GAUSSIAN 98 code without any symmetry constraint. While the ground-state geometries and their corresponding binding energies obtained from ab initio calculations do not differ much from those obtained using the molecular-dynamics approach, the relative stability of the clusters and the energy gap between the highest occupied and the lowest unoccupied molecular orbitals show significant differences. The energy gaps, calculated using the density-functional theory, show distinct shell closure effects, namely, sharp drops in their values for Be clusters containing 2, 8, 20, 34, and 40 electrons. While these features may suggest that small Be clusters behave free-electron-like and, hence, are metallic, the evolution of the structure, binding energies, coordination numbers, and nearest-neighbor distances do not show any sign of convergence towards the bulk value. We also conclude that molecular-dynamics simulation based on many-body interatomic potentials may not always give the correct picture of the evolution of the structure and energetics of clusters although they may serve as a useful tool for obtaining starting geometries by efficiently searching a large part of the phase space.

Journal Article↗

PubMed2004

Obstructive sleep-disordered breathing with a dominant cyclic alternating pattern--a recognizable polysomnographic variant with practical clinical implications.

OBJECTIVES: To define the clinical and polysomnographic features of a distinct variant of obstructive sleep-disordered breathing that is remarkably mild during rapid eye movement (REM) sleep. DESIGN: Observational study and evaluation of polysomnographic and clinical records. SETTING: American Academy of Sleep Medicine-accredited multidisciplinary sleep disorders center and laboratory. PATIENTS: 35 medication-free subjects with clinical and polysomnographic severe obstructive sleep-disordered breathing selected for dominance of 1 of 2 disordered breathing patterns. INTERVENTIONS: Positive airway pressure titration. MEASUREMENTS AND RESULTS: Nasal pressure was used to score respiratory events. Sleep was scored by both the standard criteria and cyclic alternating pattern (CAP), and the distribution of respiratory events was tabulated and analyzed. A distinct clinical and polysomnographic syndrome emerged, CAP-dominant sleep-disordered breathing, characterized by severe relatively short cycle obstructive events during non-REM sleep that were mild in REM sleep. Characteristics include lower body mass index, fewer apneas, and a lower hypoxic burden as reflected by frequency and severity of nocturnal oxygen saturation. During positive pressure titration, a remarkable respiratory instability emerged selectively during CAP, in contrast to stability during REM sleep. This partial treatment failure was associated with persistent clinical symptoms. CONCLUSIONS: This variant of sleep apnea may reflect a dominant component of respiratory instability and periodic breathing coupled with upper-airway obstruction. Its existence questions the conventional practice of calculating global respiratory indexes. Besides positive airway pressure, measures to treat periodic breathing may be required.

Electroencephalography↗

PubMed1991

Stability of medical specialty selection at the University of Kentucky.

In the fall of 1989, all graduates of a 30-year-old medical college were surveyed by questionnaire concerning their motivations for their original selections of specialties, motivations for changing their specialties when such changes had occurred, and factors involved in their current choices of specialties. The 723 respondents were grouped by specialty response into one of three groups (primary care plus medicine and pediatrics subspecialties; surgery; or controllable lifestyle), and responses were statistically analyzed. The most important factors influencing initial specialty selection were perceived match of personality and specialty; technology and methodology characteristic of the specialty; and time for family activities, in that order. The ratings of the 175 respondents who stated that they had changed specialties indicated that time for avocational pursuits and time for family activities were the most important reasons for change. The reasons for selecting a different specialty varied. This study's findings suggest that a student's likelihood of making an inappropriate specialty choice may be reduced by a broad undergraduate medical education with realistic experiences in clinical activity. Students' lack of awareness of the lifestyle of a particular specialty may be a significant factor in the flow of physicians from noncontrollable lifestyle specialty areas. Those who counsel medical students need to be aware of the increasing importance of controllable lifestyle features, changing attitudes, faculty role-modeling, and mentors as strong influences on students' choices of specialties.

Career Choice↗

PubMed2002

Flexible and frozen sugar-modified nucleic acids--modulation of biological activity through furanose ring dynamics in the antisense strand.

A comparison of carbohydrate modified nucleic acids has identified key structural characteristics in antisense oligonucleotides (AON) that are necessary for sufficient clinical utility, including increased duplex stability towards RNA complements and improved hydrolytic resistance towards general serum and cellular nucleases. As such, the exogenous addition of short, synthetic oligonucleotides can influence cellular RNA metabolism at any or all levels of replication, transcription or translation by tight and specific hybridization with a chosen target and subsequently stop further function at that site. Furthermore, appropriate modification of the sugar residue may prove to be a vital design element in future AONs that operate by promoting enzyme assisted catalytic destruction of the mRNA target. Unfortunately, many of the current AON designs have provided little insight on the particular structural role of the AON towards enzymatic discrimination of the resultant hybrid. The use of RNase H as a cellular vehicle to assist the inhibitory potency of an AON as well as possible ways of enhancing activity in pre-existing antisense candidates are presented. Of the emerging criteria in this aspect, a balance between flexibility and rigidity within the AON appears to be a critical mediator of the RNase H assisted antisense effect. Accordingly, this review describes the conformational features and selected biological attributes of some of the more prominent AON contenders with a focus on the conformational criteria by which ribonuclease H activity is recruited to a particular hybrid target.

Humans↗

PubMed1989

Analysis of machine-selected cells with an image analysis system in normal and abnormal cervical specimens.

An analysis has been performed of visual diagnostic criteria used in cervical cytology applied to machine selected cells in relation to automated classification based on variables, which can be recorded in an image system with automated cell search and segmentation, feature extraction and classification. A 98% accuracy could be obtained with the choice of the most ideal statistical methods for discrimination and the use of the most powerful variables recorded in the image system when compared with consensus of the visual diagnoses based on established cytological criteria for diagnosis of cancer and precancer of the cervix uteri. The most powerful discriminatory variables in the image system (of 17 recorded) for discrimination between normal and abnormal epithelial cells were, in addition to nuclear extinction, cytoplasmic extinction and cytoplasmic shape. It is concluded that the visual classification of cervical cells is highly accurate with experienced observers and that imaging microscopes can be trained to nearly equal this accuracy with appropriate statistical methods of discrimination. The problem of creating fully automated systems, however, also requires the inclusion of even more effective discriminatory variables and also the solution of such problems as automatic cell search, segmentation, artifact rejection, feature extraction, classification and electronic stability in order to become cost-effective.

Cervix Uteri↗

PubMed2001

Piffalls in diagnostic molecular pathology--significance of sampling error.

Today, molecular diagnostic tests are widely used in clinical medicine with polymerase chain reaction (PCR)-based techniques being of particular interest. In tissue specimens, however, false-positive and false-negative results can be obtained if pathomorphological and processing aspects are not considered. We therefore studied the impact of tissue sampling in three widely used diagnostic tests: (1) assessment of clonality in B-cell non-Hodgkin's lymphoma, (2) analysis of microsatellite instability (MSI) in colorectal neoplasia, and (3) demonstration of mycobacterium tuberculosis. Tissue sections of routinely formalin-fixed and paraffin-embedded diagnostic specimens were taken, and the significance of sampling was systematically investigated using laser microdissection or processing of the entire section. PCR analyses were done according to standard protocols. False-positive pseudo-monoclonality was obtained in small gastrointestinal biopsies and in laser microdissected lymph follicles of non-neoplastic tonsils. False negativity (pseudo-stability) could be demonstrated in a case with hereditary rectal adenoma if whole tissue sections were taken without microdissection of the most dysplastic subareas. Demonstration of mycobacteria failed in tissue sections of a formalin-fixed lymph node that was positive after complete digestion or in fresh frozen material of the same patient. In diagnostic molecular pathology, sampling error is an important source of false-positive and false-negative results, particularly if disease- and tissue-specific morphological features, such as sample size, type of fixation, and intralesional heterogeneity, are ignored.

Clone Cells↗

PubMed2000

Development of protegrins for the treatment and prevention of oral mucositis: structure-activity relationships of synthetic protegrin analogues.

Protegrin antimicrobial peptides possess activity against gram-positive and gram-negative bacteria and yeasts. An extensive structure-activity relationship (SAR) study was conducted on several hundred protegrin analogues to gain understanding of the relationship between the primary and secondary structure of the protegrins and their antimicrobial activities, and to identify a protegrin analogue for clinical development. Native sequence protegrins are cationic, amphiphilic peptides that are characterized by the presence of a beta-sheet structure that is maintained by two disulfide bridges. The presence of the beta-sheet is key to the stability of the protegrin structure; linearized analogues or analogues that have amino acid substitutions that eliminate hydrogen bonding across the beta-sheet have reduced activity, especially in the presence of physiological concentrations of NaCl. Also, maintaining amphiphilicity of the beta-sheet is key; analogues with substitutions of polar amino acids in the hydrophobic face have reduced activity. Analogues with reduced positive charge tend to be less active, an observation that is more marked for gram-negative than gram-positive bacteria, and may implicate binding to lipopolysaccharide as a key mechanistic step in the killing of gram-negative bacteria. A very large number of amino acid substitutions are tolerated by the protegrin structure, implying that overall structural features such as amphiphilicity, charge, and shape are more important to activity than the presence of specific amino acids. This lack of importance of specific stereochemistry is supported by the fact that completely D-amino acid substituted protegrins are fully potent. Based on the SAR studies, and on the microbiological data from an animal model, one protegrin analogue, IB-367, was selected for clinical development as a topical agent to prevent the oral mucositis associated with cancer therapy.

Amino Acid Sequence↗

PubMed1996

Molecular dynamics of amphotericin B. II. Dimer in water.

Molecular dynamics simulations were performed for a dimer of the antifungal antibiotic, amphotericin B, in water. In the first step of the work three appropriately selected versions of the dimer structure were taken into consideration. In each version antibiotic molecules were placed antiparallel with polar and ionizable groups outside the hydrophobic core formed by polyene chromophores. During short dynamic simulations versions of the dimer structure were compared in respect of the energy of dimerization. The highest energy was observed for the structure in which polyene chromophores superimposed each other as much as possible and this version was subjected to the main simulation. The analysis of 66 snapshot geometries stored during 33 ps dynamic trajectory allowed us to draw three main conclusions: (i) the relative orientation of the amino-sugar moiety and chromophore as well as conformation of the antibiotic macrolide ring were different in both molecules and could exhibit dynamic changes, (ii) the dimer structure exhibited intrinsic asymmetry which could be responsible for characteristic circular dichroism spectra of the aggregated form of the antibiotic, (iii) relatively high stability of the dimer structure resulted not only from hydrophobic interactions between chromophores but also from hydrogen bonds networks that were observed around polar terminals of antibiotic molecules. Implications of these features of the dimer structure for its susceptibility on the ionic state of carboxyl and/or amino groups are also discussed.

Amphotericin B↗

PubMed2002

Testosterone increases perceived dominance but not attractiveness in human males.

Recent evidence suggests that certain features on the human face indicate hormonal levels during growth, and that women judge the attractiveness of potential partners based on the appearance of these features. One entrenched notion is male facial features that are affected by testosterone are used as direct cues in mate preference. Testosterone may be particularly revealing as it is purported to be an honest indicator of male fitness. Increased testosterone may impose an immunocompetence handicap on the bearer and only the best males can carry this handicap. To date, tests of this theory have been indirect, and have relied on digital manipulations that represent unrealistic continuums of masculine and feminine faces. We provide a much more direct test by manipulating digitally male faces to mimic known shape variation, caused by varying levels of testosterone through puberty. We produced a continuum of faces that ranged from low to high levels of testosterone in male faces and asked women to choose the points on the continuum that appeared most attractive and most physically dominant. Our data indicate that high testosterone faces reveal dominance. However, there is no evidence of directional selection for increased (or decreased) testosterone in terms of attractiveness to the opposite sex. We discuss the relevance and applicability of evolutionary interpretations of our data and, contrary to predictions, provide evidence of stabilizing selection acting on testosterone through mate preferences.

Adolescent↗

PubMed2003

[The chemistry of pericyclic reactions and their application to syntheses of heterocyclic compounds].

Diels-Alder reactions of benzylidenecyanomethyl-1,3-benzothiazoles 17 and -1,3-benzoxazoles 18 as 1-aza-1,3-butadienes are described. The dienes 17 and 18 featuring stabilized imine moieties in the form of heteroaromatic rings react with both electron-deficient and electron-rich dienophiles to give corresponding cycloadducts regioselectively. The cycloadditions of the intramolecular systems 34c,d and 35c,d proceeded smoothly via the exo-transition state, stereoselectively affording polycyclic compounds 36c,d and 37c,d in good to excellent yields. The diene systems of 17 and 18 were extended to dienes 19a-c with ester groups at diene-4-positions. Dienes 19a-c exhibited high Diels-Alder reactivities with electron-rich alkenes. Dienes 19a-c also reacted with allyl alcohols 55-58 in the presence of stanoxane catalyst 53 to give cycloadducts 59-62 via transesterification and intramolecular cycloaddition. Although alpha-alkoxycarbonylnitrones 64 have been very attractive nitrones for the syntheses of amino acids, the nitrones 64 exist as equilibrating mixtures of (E)-64 and (Z)-64. To solve this problem, three methods were explored: 1) sequential transesterification and intermolecular cycloaddition of nitrones 64 with allyl alcohols; 2) use of chiral and geometry-fixed nitrone 84; and 3) selective activation of (Z)-64 by Eu(fod)3. These methods were applied to syntheses of nikkomycins, clavalanine, and beta-substituted alpha-amino acids. The reactions of photoinduced carbonyl ylides from alpha,beta-unsaturated gamma,delta-epoxy nitriles were studied. Direct irradiation (lambda = 254 nm) of (E)-129 led selectively to products arising from the carbonyl ylide XXV or the carbene intermediate XXVI. The carbonyl ylides generated from (E)-129, (E)-139, and (Z)-143 were trapped with MeOH in the presence of amine, affording the corresponding acetals in moderate yields (Schemes 42 and 43). Photocyclization reactions of delta-hydroxyalkyl epoxy nitriles 148a-e led to spiro acetals arising from the carbonyl ylides (Scheme 45). The photoinduced carbonyl ylides from the epoxy dinitriles 158 and 160-163 underwent 1,3-dipolar cycloaddition with enol ethers, leading to a tetrahydrofuran system (Schemes 49 and 50, Table 14). Electrocyclization of 3-butadienylindoles 184 to intermediary dihydrocarbazoles XXXII followed by elimination of MeOH gave 3-oxyganated carbazoles 185, which were transformed to carbazole alkaloids hyellazole 168, 4-demethoxycarbazomycin B 170 and carazostatin 171, respectively. Claisen rearrangement of 3-(1-amino-1-vinyloxy) indolines derived from 3-hydroxyindolines 192 and amide acetal 193 gave indol-4-ylacetamides 194, which was reduced to afford 4-(2-aminoethyl) indoles 198, which has a framework of biologically active 4-substituted indole compounds. Claisen rearrangement of 3-allyloxyindoles produced in situ by condensation of indolin-3-ones 202 with allyl alcohols 203 and 206-211 gave 2-allylindolin-3-ones 204, 205 and 212-220. The domino reactions, Horner-Wadsworth-Emmons olefination of 2-allyloxyindole 233, isomerization, and Claisen rearrangement produced 3-allylindolin-2-one 234, which was derivatized to 3a-allylpyrrolo [2,3-b] indole alkaloid, flustramine C 221. Reverse aromatic Cope rearrangement of 2-allyl-3-indolidene acetonitriles 241-243, formed by Horner-Wadsworth-Emmons reaction of 2-allylindolin-3-ones 238-240, afforded indoles 244-246.

Aza Compounds↗

PubMed2005

Quantitative study of electrostatic and steric effects on physicochemical property and biological activity.

The physicochemical properties and biological activities are highly dependent on the electrostatic and steric effects of compounds. The characterization of these structural features will help to elucidate the quantitative structure-property/activity relationship (QSPR/QSAR). In this paper, two novel structural descriptors, lone-pair electrons index (LEI) and molecular volume index (MVI) were developed to quantify the molecular electrostatic and steric effects, respectively. One of the most attractive traits of these two descriptors is that the calculation is very easy, especially for LEI, which only takes the heteroatoms into account. Four data sets on diverse physicochemical properties and biological activities were selected as examples to evaluate the utility of these descriptors. One or two-variable multiple linear regression (MLR) models against the four data sets obtained such correlation results as follows: correlation coefficient R = 0.9998 and standard deviation s = 0.095 for the partition coefficient of halide benzenes; R = 0.9689 and s = 0.248 for the toxicity of heterocyclic nitrogen-containing compounds to miracidium; R = 0.9645 and s = 0.209 for the antifungal activity of benzyl alcohols to aspergillus niger; R = 0.9530 and s = 0.206 for the toxicity of substituted phenols against tetrahymena pyriformis. Leave-one-out cross validation was also carried out to evaluate the stability of each model and good results were obtained.

Animals↗

PubMed2000

Pathological gambling.

With increasing access to gambling facilities through casinos, the Internet, and other venues, PG is a rapidly emerging mental health concern. This impulse-control disorder tends to be comorbid with a wide range of other disorders and is reportedly associated with a high rate of suicide. For most gamblers, gambling is a form of entertainment, but for many individuals, the activity leads to far-reaching disruption of family and work. The personal and societal financial ramifications are severe, and many individuals with PG end up in the criminal justice system. An understanding of the neurobiology of PG is beginning to surface. 5-HT is linked to behavioral initiation and disinhibition, which are important in the onset of the gambling cycle and the difficulty in ceasing the behavior. Norepinephrine is associated with the arousal and risk taking in patients with PG. Dopamine is linked to positive and negative reward, the addictive component of this disorder. Effective treatment strategies for pathological gamblers are emerging. Potentially useful pharmacologic agents include SRIs (clomipramine and fluvoxamine), mood stabilizers for pathological gamblers with comorbid bipolar disorders (lithium), and naltrexone. Cognitive-behavioral psychotherapies offer promising results in the treatment of patients with this disorder. To devise prevention and early-intervention programs, research is needed to identify specific features of the individuals at risk for gambling problems. Education targeting vulnerable youth that show early signs of gambling behavior may be worthwhile and should be investigated further. Funding is necessary to support these endeavors, so perhaps a portion of tax revenues generated from the gambling industry should go toward specialized treatment facilities, educational efforts, and research into the neurobiology and treatment of PG.

Cognitive Behavioral Therapy↗