Functionalized benzophenone, thiophene, pyridine, and fluorene thiosemicarbazone derivatives as inhibitors of cathepsin L

A series of thiosemicarbazone analogs based on the benzophenone, thiophene, pyridine, and fluorene molecular frameworks has been prepared by chemical synthesis and evaluated as small-molecule inhibitors of the cysteine proteases cathepsin L and cathepsin B. The two most potent inhibitors of cathepsin L in this series (IC(50)<135 nM) are brominated-benzophenone thiosemicarbazone analogs that are further functionalized with a phenolic moiety (2 and 6). In addition, a bromo-benzophenone thiosemicarbazone acetyl derivative (3) is also strongly inhibitory against cathepsin L (IC(50)=150.8 nM). Bromine substitution in the thiophene series results in compounds that demonstrate only moderate inhibition of cathepsin L. The two most active analogs in the benzophenone thiosemicarbazone series are highly selective for their inhibition of cathepsin L versus cathepsin B.     

HLA antigen,gene, and haplotype frequencies in Thailand

Summary Antigen, gene, and haplotype frequencies as well as phenotype distribution of the HLA system were studied in a series of 213 individuals in northern Thailand. The series consisted of 160 northern Thais, 23 Thai individuals from various other regions of Thailand, and 25 persons of Chinese origin. Most frequently found were the alleles HLA-A11 and HLA-Bw40 and the haplotype HLA-A2, B-. Phenotype distribution followed a Hardy-Weinberg expectation. Significant differences were found especially between our results for the alleles of locus B and the results of a series from Bangkok reported by Chiewsilp and Chanarat (1976).     

Synthesis of enantiomerically pure milnacipran analogs and inhibition of dopamine, serotonin, and norepinephrine transporters

A series of Milnacipran analogs with variation in the aromatic moiety were prepared in high enantiomeric excess. Structure-activity relationships for two parallel enantiomeric series are described. The (-)-(1R,2S)-naphthyl analog (8h) showed the highest potency in the two series and is a triple reuptake inhibitor of the SERT, NET, and DAT.     

Indeno[1,2-c]isoquinolin-5,11-diones conjugated to amino acids: Synthesis, cytotoxicity, DNA interaction, and topoisomerase II inhibition properties

Three series of indeno[1,2-c]isoquinolin-5,11-dione-amino acid conjugates were designed and synthesized. Amino acids were connected to the tetracycle through linkers with lengths of n=2 and 3 atoms using ester (series I), amide (series II), and secondary amine (series III) functions. DNA binding was evaluated by thermal denaturation and fluorescence measurements. Lysine and arginine substituted derivatives with n=3 provided the highest DNA binding. Arginine derivative 32 (n=2, series II) and glycine derivative 34 (n=2, series III) displayed high topoisomerase II inhibition. Incrementing the length of the N-6 side chain from two to three methylene units provided a significant increase in DNA affinity but a substantial loss in topoisomerase II inhibition. The most cytotoxic compounds toward HL60 leukemia cells were 19, 33, and 34 displaying micromolar IC(50) values. When tested with the topoisomerase II-mutated HL60/MX2 cell line, little variation of IC(50) values was found, suggesting that topoisomerase II might not be the main target of these compounds and that additional targets could be involved.     

Prodrug-based design, synthesis, and biological evaluation of N-benzenesulfonylpiperidine derivatives as novel, orally active factor Xa inhibitors

We describe here our investigation of a new series of orally active fXa inhibitors based on a prodrug strategy. Solid-phase parallel synthesis identified a unique series of fXa inhibitors with a substituted benzenesulfonyl group as a novel S4 binding element. This series resulted in compound 39, which exhibited potent inhibitory activity against fXa (IC50 = 13 nM) and excellent selectivity over thrombin (>7000-fold). The masking of its highly hydrophilic groups led to the creation of related prodrug 28, which demonstrated an anticoagulant effect after oral dosing.     

The antimicrobial activity of mono-, bis-, tris-, and tetracationic amphiphiles derived from simple polyamine platforms

A series of 34 amphiphilic compounds varying in both number of quaternary ammonium groups and length of alkyl chains has been assembled. The synthetic preparations for these structures are simple and generally high-yielding, proceeding in 1–2 steps without the need for chromatography. Antibacterial MIC data for these compounds were determined, and over half boast single digit MIC values against a series of gram-positive and gram-negative bacteria. MIC variation mostly hinged on the length of the alkyl chain, where a dodecyl group led to optimal activity; surprisingly, the number of cations and/or basic nitrogens was less important in dictating bioactivity. Additional structural variation was prepared in a trisamine series dubbed 12,3,X,3,12, providing a series of potent amphiphiles functionalized with varied allyl, alkyl, and benzyl groups. Tetraamines were also investigated, culminating in a two-step preparation of a tetracationic structure that showed only modestly improved bioactivity versus amphiphiles with two or three cations.     

Novel glucocorticoids containing a 6,5-bicyclic core fused to a pyrazole ring: synthesis, in vitro profile, molecular modeling studies, and in vivo experiments

Chemistry was developed to synthesize the title series of compounds. The ability of these novel ligands to bind to the glucocorticoid receptor was investigated. These compounds were also tested in a series of functional assays and some were found to display the profile of a dissociated glucocorticoid. The SAR of the 6,5-bicyclic series differed markedly from the previously reported 6,6-series. Molecular modeling studies were employed to understand the conformational differences between the two series of compounds, which may explain their divergent activity. Two compounds were profiled in vivo and shown to reduce inflammation in a mouse model. An active metabolite is suspected in one case.     

Polycyclic nitrogen heterocycles as potential thymidine phosphorylase inhibitors: synthesis,biological evaluation,and molecular docking study

New polycyclic heterocycles were synthesised and evaluated as potential inhibitors of thymidine phosphorylase (TP). Inspired by the pharmacophoric pyrimidinedione core of the natural substrate, four series have been designed in order to interact with large empty pockets of the active site: pyrimidoquinoline-2,4-diones (series A), pyrimidinedione linked to a pyrroloquinoline-1,3-diones (series B and C), the polycyclic heterocycle has been replaced by a pyrimidopyridopyrrolidinetetraone (series D). In each series, the tricyclic nitrogen heterocyclic moiety has been synthesised by a one-pot multicomponent reaction. Compared to 7-DX used as control, 2d, 2l, 2p (series A), 28a (series D), and the open intermediate 30 showed modest to good activities. A kinetic study confirmed that the most active compounds 2d, 2p are competitive inhibitors. Molecular docking analysis confirmed the interaction of these new compounds at the active binding site of TP and highlighted a plausible specific interaction in a pocket that had not yet been explored.     

Healed fractures in Macaca mulatta: age, sex, and symmetry.

Previous studies utilizing series of wild-shot primates have suggested that there is an association between locomotor behavior, aggression and patterning of healed fractures. In this study, observations taken upon a series of 126 rhesus macaques which represent a total sample of a naturally occurring social group from Cayo Santiago, are used to reexamine the conclusions drawn from previous studies. As a control, a series of randomly collected rhesus skeletons from the same colony is examined. Major differences in pathology incidences by age, sex and laterality is indicated between the two groups. Possible explanation for cross-specific variability in fracture patterning are also considered.     

Design, synthesis, and structure-activity relationships of piperidine and dehydropiperidine carboxylic acids as novel, potent dual PPARalpha/gamma agonists

Several series of substituted dehydropiperidine and piperidine-4-carboxylic acid analogs have been designed and synthesized as novel, potent dual PPARalpha/gamma agonists. The SAR of these series of analogs is discussed. A rare double bond migration occurred during the basic hydrolysis of the alpha,beta-unsaturated dehydropiperidine esters 12, and the structures of the migration products were confirmed through a series of 2D NMR experiments.     

Resolvins, docosatrienes, and neuroprotectins, novel omega-3-derived mediators, and their aspirin-triggered endogenous epimers: an overview of their protective roles in catabasis

The molecular basis for the beneficial impact of essential omega-3 fatty acids is of considerable interest. Recently, novel mediators generated from eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) that displayed potent bioactions were first identified in resolving inflammatory exudates [J. Exp. Med. 192 (2000) 1197; J. Exp. Med. 196 (2002) 1025] and in tissues enriched with DHA [J. Exp. Med. 196 (2002) 1025; J. Biol. Chem. 278 (2003) 14677]. The trivial names Resolvin (resolution phase interaction products) and docosatrienes were introduced for the bioactive compounds belonging to these novel series because they demonstrate potent anti-inflammatory and immunoregulatory actions. The compounds derived from eicosapentaenoic acid carrying potent biological actions (i.e., 1-10 nM range) are designated E series, given their EPA precursor, and denoted as Resolvins of the E series (Resolvin E1 or RvE1), and those biosynthesized from the precursor docosahexaenoic acid are Resolvins of the D series (Resolvin D1 or RvD1). Bioactive members from DHA with conjugated triene structures are docosatrienes (DT) that are immunoregulatory [J. Exp. Med. 196 (2002) 1025; J. Biol. Chem. 278 (2003) 14677], and neuroprotective [J. Biol. Chem., 278 (2003) 43807; Proc. Natl. Acad. Sci. U.S.A. [submitted for publication]] and are termed neuroprotectins. The specific receptors for these novel bioactive products from omega-3 EPA and DHA are abbreviated Resolvin D receptors (i.e., ResoDR1), Resolvin E receptor (ResoER1; RER1), and neuroprotectin D receptors (NPDR), respectively, in recognition of their respective cognate ligands. Aspirin treatment impacts biosynthesis of these compounds and a related series by triggering endogenous formation of the 17R-D series Resolvins and docosatrienes. These novel epimers are denoted as aspirin-triggered (AT)-RvDs and -DTs, and possess potent anti-inflammatory actions in vivo essentially equivalent to their 17S series pathway products. Here, we provide a syntomy overview of the formation and actions of these newly uncovered pathways and products as well as highlight their role(s) as endogenous protective mediators generated in anti-inflammation and catabasis.     

Leg crossing, muscle tensing, squatting, and the crash position are effective against vasovagal reactions solely through increases in cardiac output.

Tensing of lower body muscles without or with leg crossing (LBMT, LCMT), whole body tensing (WBT), squatting, and sitting with the head bent between the knees ("crash position", HBK) are believed to abort vasovagal reactions. The underlying mechanisms are unknown. To study these interventions in patients with a clinical history of vasovagal syncope and a vasovagal reaction during routine tilt table testing, we measured blood pressure (BP) continuously with Finapres and derived heart rate, stroke volume, cardiac output (CO), and total peripheral resistance using Modelflow. In series A (n = 12) we compared LBMT to LCMT. In series B (n = 9), WBT was compared with LCMT. In series C (n = 14) and D (n = 9), we tested squatting and HBK. All maneuvers caused an increase in BP, varying from a systolic rise from 77 +/- 8 to 104 +/- 18 mmHg (P < 0.05) in series A during LBMT to a rise from 70 +/- 10 to 123 +/- 9 mmHg (P < 0.05) in series B during LCMT. In each maneuver, the BP increase started within 3-5 s from start of the maneuver. In all maneuvers, there was an increase in CO varying from 54 +/- 12% of baseline to 94 +/- 21% in WBT to a rise from 65 +/- 17% to 110 +/- 22% in LCMT in series A. No maneuver caused significant change in total peripheral resistance. We conclude that the mechanism underlying the effects of these maneuvers is exclusively an increase in CO.     

Genes,culture, and the human niche: An overview

The sharp distinction between biological traits and culturally based traits, which had long been standard in evolutionary approaches to behavior, was blurred in the early 1980s by mathematical models that allowed a co‐dependent evolution of genetic transmission and cultural information. Niche‐construction theory has since added another contrast to standard evolutionary theory, in that it views niche construction as a cause of evolutionary change rather than simply a product of selection. While offering a new understanding of the coevolution of genes, culture, and human behavior, niche‐construction models also invoke multivariate causality, which require multiple time series to resolve. The empirical challenge lies in obtaining time‐series data on causal pathways involved in the coevolution of genes, culture, and behavior. This is a significant issue in archeology, where time series are often sparse and causal behaviors are represented only by proxies in the material record.     

'Proteomic basics--sample preparation and separation': the 1st European Summer School in Kloster Neustift, 12-18 August, 2007 Brixen/Bressanone, South Tyrol, Italy

Proteomics is rapidly developing into a routine approach for protein analysis in many laboratories. The series of European-wide Summer Schools 'Proteomics Basics' (http://www.proteomic-basics.eu/) aims at teaching of comprehensive knowledge in proteomics research and applied technologies for master and graduate students and postdocs currently moving into the field of proteomic research. In the next 3 years the series will cover the theoretical basis of the fundamental topics in the various areas of proteomic analysis, i.e. sample preparation and handling, mass spectrometry, post-translational modifications and quantitation given by leading experts in the field. This summer school series embodies a unique advantage in comparison with conventional scientific meetings and university curricula: internationally renowned experts will give a detailed perspective view of the fundamentals of their particular proteome research area, something which is usually not encountered at conferences and congresses. Here, we give a report on the first European Summer School 'Sample Preparation and Handling' within the series 'Proteomic Basics' that was held at the monastery in Neustift close to Bressanone/Brixen, Italy from August 12 to 18, 2007.     

Study of skin anti-ageing and anti-inflammatory effects of dihydroquercetin, natural triterpenoinds, and their synthetic derivatives

Accessible triterpenoids of ursane and lupane series, the flavonoid dihydroquercetin and their synthetic derivatives with polar substituents were tested in vitro for inhibition of collagenase 1 (MMP-1) in UVB irradiation assay. Ursolic acid and uvaol disuccinate were the most active inhibitors in the ursane series. In the lupane series, the best inhibition was manifested by carboxymethyl ester of betulonic acid and betulin succinates. Down- regulation of MMP-1 by dihydroquercetin and its synthetic derivatives surpassed the activity of a standard (retinoic acid).     

Cytokinins and Differentiation Processes in Mercurialis annua: Genetic Regulation, Relations with Auxins, Indoleacetic Acid Oxidases, and Sexual Expression Patterns

Cytokinins in apices of eight isogenic lines of Mercurialis annua were compared (high performance liquid chromatography-gas chromatography mass spectroscopy-computer system). These apices develop normal staminate or pistillate differentiation processes (sex series lines) or empty (sterile), semiempty (semisterile), and full anthers (restored fertile male) in the sterility series in which a pistillate line was constructed. Both series developed two different cytokinin pathways: trans-cytokinins characterized the sex series, whereas the cis pathway characterized the sterility series. Drastic changes in the trans pathway (0/250 nanograms trans-zeatin and 166/0 nanograms zeatin nucleotide) induced staminate/pistillate differentiations. Less drastic quantitative changes in the cis pathway induced sterility or restored fertility compared to normal fertile anthers (192 or 669 nanograms/traces). The action of the complete cis-pathway was morphologically effective in the sterility series when the ratio of cis to trans pathways was 1:2 or 1:1 instead of 1:3. A final diagram shows the action of each sex or sterility allele on the enzymes controlling specific metabolites in both pathways. The discussion provides insights on the regulation of cytokinin-auxin balances specific for each kind of reproductive differentiation.     

Design and optimization of potent, selective antagonists of Oxytocin

A novel series of Oxytocin antagonists are described. This series was identified through pharmacophoric overlap of in-house and literature antagonists. Subsequent optimization led to a series of potent, selective antagonists. Several analogues displayed oral bioavailability in vivo in the rat.     

Design, synthesis, and studies of small molecule STAT3 inhibitors

A series of small molecule STAT3 inhibitors originally derived from our lead compound STA 21 were synthesized and evaluated. The most potent compound in this series, compound 1, exhibited the same anti-proliferative activities as STA 21 against prostate cancer cell lines that express constitutively active STAT3. Molecular docking showed compound 1 bound to the STAT3beta SH2 domain in a similar manner as STA 21.     

Nearest-neighbor and next-nearest-neighbor effects in the proton NMR spectra of the oligoribonucleotides ApXpG,CpXpG, CpApXpUpG,ApGpXpC, and ApGpXpCpU

The proton nmr spectra of the oligoribonucleotides in the series CpXpG, ApXpG, CpApXpUpG, and ApGpXpC (X = A, G, C, and U), together with the reference compounds CpG, ApG, CpApUpG, and ApGpC, have been measured. A complete analysis of all the nonexchangeable base protons and the ribose H-1′ protons was made. The insertion of a nucleotide X into a oligoribonucleotide led to shift changes at both nearest-neighbor and next-nearest-neighbor positions, which were rationalized in terms of the shielding abilities of the various bases. The derived shielding trends in the ApGpXpC series of compounds were successfully used to predict the chemical shifts of resonances in the related ApGpXpCpU series.