One Bead-One Compound (OBOC) Peptidomimetic-Encoded Library Synthesis via Split-and-Pool Methods.

Large structurally diverse peptidomimetic chemical libraries have been very useful tools in chemical biology and drug discovery for the identification of therapeutically important compounds with higher affinity and improved pharmacological properties against different protein targets.Here we describe a simple and general method for the submonomer solid phase synthesis of large one bead-one compound (OBOC) peptidomimetic libraries of structurally diverse compounds that can be encoded by mass or genetic methods.

Prevalência do Uso de Álcool, Tabaco e Hipnóticos/Sedativos por Idosos Atendidos em Estratégias de Saúde da Família / Prevalence of Alcohol, Tobacco and Hypnotic/Sedative use by the Elderly in Family Health Strategies

Introdução: A população idosa está crescendo cada vez mais, e esse aumento da longevidade traz consigo a percepção sobre os prejuízos no acúmulo de carga tabágica e alcoólica. O idoso acumula também comorbidades que requerem medicações prescritas. Destaca-se o uso de hipnóticos/sedativos nesta população. Métodos: Estudo observacional com delineamento transversal prospectivo em indivíduos com 60 anos ou mais atendidos em três unidades de Estratégias de Saúde da Família. Resultados: Foram avaliados 350 idosos sendo a maioria da amostra composta por mulheres (61,1%), com a mediana de idade de 69,0, maioria era de casadas (53,7%), ensino fundamental incompleto (57,1%), aposentadas (68%) e com renda menor que 3 salários mínimos (56%). Dos entrevistados, 21,4% apresentavam transtorno depressivo maior, 16,9% transtorno de ansiedade generalizada e 48,0% insônia. 38,6% dos idosos, faziam uso de hipnóticos/sedativos, com prevalência de benzodiazepínicos (28%), 34% das pessoas fizeram uso de bebidas alcoólicas e 14,3%, de cigarros. Conclusão: Foi possível concluir que a população com maior prevalência sobre o uso de álcool, tabaco e hipnóticos/sedativos foi de mulheres, casadas, aposentadas, de baixa renda e baixa escolaridade. Tanto no álcool quanto no tabaco, o homem necessita mais de intervenção. Quando são analisadas ambas as substâncias, percebe-se que 54% dos que fumaram nos últimos 3 meses também ingeriram bebidas alcoólicas. Existe uma relação íntima entre as comorbidades estudadas e o uso de hipnóticos/sedativos, visto que estes são utilizados na maioria dos tratamentos dessas doenças. Tal relação já não foi possível ser feita com álcool e tabaco.

Introduction: The elderly population is growing progressively, and this increase in longevity brings with it the perception of the damages of accumulating a tobacco and alcohol load. The elderly also develop comorbidities that require prescribed medications. The use of hypnotics/sedatives in this population stands out. Method: observational study with prospective cross-sectional design in individuals aged 60 years or older seen at three Family Health Strategy units. Results: After evaluating 350 elderly, most of the sample was composed of women (61.1%), with a median age of 69.0, most were married (53.7%), had incomplete elementary school education (57.1%), were retired (68%) and had an income of less than three minimum wages (56%). Of the interviewed, 21.4% had major depressive disorder, 16.9% had generalized anxiety disorder, and 48.0% had insomnia. Also, 38.6% of the elderly used hypnotics/sedatives, with a prevalence of benzodiazepines (28%), 34% used alcoholic beverages, and 14.3% used cigarettes. Conclusion: It was possible to conclude that the population with the highest prevalence of the use of alcohol, tobacco, and hypnotics/sedatives were women, married, retired, with low income and low education. Both in alcohol and tobacco, men need more intervention. After analyzing both substances, it was clear that 54% of those who smoked in the last three months also drank alcoholic beverages. There is an intimate relationship between the comorbidities studied and the use of hypnotics/sedatives. Since these are predominant treatments for these diseases, such a relationship could not be made with alcohol and tobacco.

Relato de Caso: arco aórtico a direita com Divertículo de Kommerell / Case Report: aortic arch to the right with Kommerell's Diverticulum

RESUMO O divertículo de Kommerell é uma alteração rara que ocorre mais comumente com arco aórtico à esquerda e origem anômala de artéria subclávia direita (0,5%-2,0%). Em geral é assintomático, com sintomas relacionados a cardiopatias congênitas quando presentes. PALAVRA-CHAVE: Ultrassonagrafia pré-natal, desenvolvimento fetal, anormalidades congênitas

ABSTRACT Kommerell's diverticulum is a rare disorder that most commonly occurs with a left aortic arch and anomalous origin of the right subclavian artery (0.5%- 2.0%). It is usually asymptomatic, with symptoms related to congenital heart disease when present. KEYWORDS: Prenatal ultrasonography, fetal development, congenital abnormalities

Synthesis of the Cortistatin Pentacyclic Core by Alkoxide-Directed Metallacycle-Mediated Annulative Cross-Coupling.

The pentacyclic core skeleton of the cortistatins has been prepared in a stereoselective fashion by strategic use of an alkoxide-directed metallacycle-mediated annulative cross-coupling. This metal-centered tandem reaction delivers a polyunsaturated hydrindane and establishes the C13 stereodefined quaternary center with high levels of stereocontrol. Subsequent regio- and stereoselective global hydroboration results in the realization of the DE-trans ring fusion and a tertiary alcohol at C8. Establishment of the ABC-tricyclic subunit was then accomplished through phenolic oxidation/trans-acetalization, chemoselective reduction, regioselective cleavage, and intramolecular alkylation at C5.

LiOOt-Bu as a terminal oxidant in a titanium alkoxide-mediated [2+2+2] reaction cascade.

LiOOt-Bu is an effective oxidant for converting the penultimate organometallic intermediate generated in a titanium alkoxide-mediated [2+2+2] reaction cascade to an allylic alcohol. Oxidation of the presumed allylic titanium species is highly regioselective, providing direct access to substituted hydroindanes containing a primary allylic alcohol. In addition to demonstrating the feasibility of this oxidation process, we document the ability to convert the primary allylic alcohol products to angularly substituted cis-fused hydroindanes.

Recognition of antigen-specific B-cell receptors from chronic lymphocytic leukemia patients by synthetic antigen surrogates.

In patients with chronic lymphocytic leukemia (CLL), a single neoplastic antigen-specific B cell accumulates and overgrows other B cells, leading to immune deficiency. CLL is often treated with drugs that ablate all B cells, leading to further weakening of humoral immunity, and a more focused therapeutic strategy capable of targeting only the pathogenic B cells would represent a significant advance. One approach to this would be to develop synthetic surrogates of the CLL antigens allowing differentiation of the CLL cells and healthy B cells in a patient. Here, we describe nonpeptidic molecules capable of targeting antigen-specific B cell receptors with good affinity and selectivity using a combinatorial library screen. We demonstrate that our hit compounds act as synthetic antigen surrogates and recognize CLL cells and not healthy B cells. Additionally, we argue that the technology we developed can be used to identify other classes of antigen surrogates.

Synthesis of angularly substituted trans-fused hydroindanes by convergent coupling of acyclic precursors.

Angularly substituted trans-fused hydroindanes are now accessible by the direct and convergent union of trimethylsilyl (TMS)-alkynes with 4-hydroxy-1,6-enynes by a process that forges three C-C bonds, one C-H bond, and two new stereocenters. The annulation is proposed to proceed by initial formation of a Ti-alkyne complex (with a TMS-alkyne) followed by regioselective alkoxide-directed coupling with the enyne, stereoselective intramolecular cycloaddition, elimination of phenoxide, 1,3-metallotropic shift, and stereoselective protonation of the penultimate allylic organometallic intermediate. Several examples are given to demonstrate the compatibility of this reaction with substrates bearing aromatic and aliphatic substituents, and an empirical model is presented to accompany the stereochemical observations.

Decoding split and pool combinatorial libraries with electron-transfer dissociation tandem mass spectrometry.

Screening of bead-based split and pool combinatorial chemistry libraries is a powerful approach to aid the discovery of new chemical compounds able to interact with, and modulate the activities of, protein targets of interest. Split and pool synthesis provides for large and well diversified chemical libraries, in this case comprised of oligomers generated from a well-defined starting set. At the end of the synthesis, each bead in the library displays many copies of a unique oligomer sequence. Because the sequence of the oligomer is not known at the time of screening, methods for decoding of the sequence of each screening "hit" are essential. Here we describe an electron-transfer dissociation (ETD) based tandem mass spectrometry approach for the decoding of mass-encoded split and pool libraries. We demonstrate that the newly described "chiral oligomers of pentenoic amides (COPAs)" yield non-sequence-specific product ions upon collisional activated dissociation; however, complete sequence information can be obtained with ETD. To aid in the decoding of libraries from MS and MS/MS data, we have incorporated (79)Br/(81)Br isotope "tags" to differentiate N- and C-terminal product ions. In addition, we have created "Hit-Find," a software program that allows users to generate libraries in silico. The user can then search all possible members of the chemical library for those that fall within a user-defined mass error.

Design, synthesis, and cytotoxic evaluation of acyl derivatives of 3-aminonaphtho[2,3-b]thiophene-4,9-dione, a quinone-based system.

A series of 3-acyl derivatives of the dihydronaphtho[2,3-b]thiophen-4,9-dione system were studied with respect to cytotoxicity and topoisomerase II inhibitory activity. These analogues were designed as electron-deficient anthraquinone analogues with potential intercalation ability. Derivatives 3-(diethylamino)-N-(4,9-dioxo-4,9-dihydronaphtho[2,3-b]thiophen-3-yl)propanamide (11m) and 3-(2-(dimethylamino)ethylamino)-N-(4,9-dioxo-4,9-dihydronaphtho[2,3-b]thiophen-3-yl)propanamide (11p) showed a high efficacy in cell lines that were highly resistant to treatment with doxorubicin, such as MDA-MB435 (melanoma), IGROV (ovarian), and SF-295 (glioblastoma) human cell lines. Both compounds inhibit topoisomerase II mediated relaxation of DNA, while only 11p incites arrest at the S phase in Caco-2 cells, inducing a delay of cell cycle progression and an increase of cell differentiation. The ability of these derivatives to modulate small heat shock proteins and cardiotoxicy effects was also explored. In addition, the DNA-binding properties of these compounds were investigated and discussed.

A biomimetic polyketide-inspired approach to small-molecule ligand discovery.

The discovery of new compounds for the pharmacological manipulation of protein function often embraces the screening of compound collections, and it is widely recognized that natural products offer beneficial characteristics as protein ligands. Much effort has therefore been focused on 'natural product-like' libraries, yet the synthesis and screening of such libraries is often limited by one or more of the following: modest library sizes and structural diversity, conformational heterogeneity and the costs associated with the substantial infrastructure of modern high-throughput screening centres. Here, we describe the design and execution of an approach to this broad problem by merging principles associated with biologically inspired oligomerization and the structure of polyketide-derived natural products. A novel class of chiral and conformationally constrained oligomers is described (termed 'chiral oligomers of pentenoic amides', COPA), which offers compatibility with split-and-pool methods and can be screened en masse in a batch mode. We demonstrate that a COPA library containing 160,000 compounds is a useful source of novel protein ligands by identifying a non-covalent synthetic ligand to the DNA-binding domain of the p53 transcription factor.

Identification of the spiro(oxindole-3,3'-thiazolidine)-based derivatives as potential p53 activity modulators.

Here, we report the design of new analogues of spirooxoindolepyrrolidine nucleus as modulators of p53 activity. Compounds (3R,7aR)-6-(4-chlorobenzyl)-1H-spiro[imidazo[1,5-c]thiazole-3,3'-indoline]-2',5,7(6H,7aH)-trione (9c) and (3R,7aR)-5'-methyl-6-(3,4,5-trimethoxybenzyl)-1H-spiro[imidazo[1,5-c]thiazole-3,3'-indoline]-2',5,7(6H,7aH)-trione (10d) are the most potent compounds of this series, inhibiting cell growth of different human tumor cells at submicromolar and micromolar concentrations, respectively. Compound 9c induces apoptotic cell death in human melanoma cell line M14 at 24 h, while in the same condition, treatment with 10d showes a clear arrest at G2/M phase inducing delay of cell cycle progression. Possibly, these activities may be due to inhibition of p53-MDM2 interaction and subsequent p53 release and activation.

A novel quinone-based derivative (DTNQ-Pro) induces apoptotic death via modulation of heat shock protein expression in Caco-2 cells.

BACKGROUND AND PURPOSE: The resistance of human colon adenocarcinoma cells to antineoplastic agents may be related to the high endogenous expression of stress proteins, including the family of heat shock proteins (HSPs). Recently, a quinone-based pentacyclic derivative, DTNQ-Pro, showed high cytotoxic activity in human colon carcinoma cell lines. The aim of the present study was to determine the precise cellular mechanisms of this cytotoxic action of DTNQ-Pro. EXPERIMENTAL APPROACH: Using human colorectal carcinoma-derived Caco-2 cells as a model, we studied the effects of DTNQ-Pro on cellular viability and oxidative stress; HSP70 and HSP27 accumulation; and cell cycle, differentiation and apoptosis. KEY RESULTS: Incubation of Caco-2 cells with DTNQ-Pro reduced cell growth and increased the levels of reactive oxygen species in mitochondria. After 48 h of treatment, cells surviving showed an increased expression of Mn-superoxide dismutase (SOD), nitric oxide production and membrane lipid peroxidation. Treatment with DTNQ-Pro decreased HSP70 expression, and redistributed HSP27 and vimentin within the cell. DTNQ-Pro down-regulated the expression of A and B cyclins with arrest of the cell cycle in S phase and increased cellular differentiation. A second treatment of Caco-2 cells with DTNQ-Pro induced cellular death by activation of the apoptotic pathway. CONCLUSIONS AND IMPLICATIONS: DTNQ-Pro causes Caco-2 cell death by induction of apoptosis via inhibition of HSP70 accumulation and the intracellular redistribution of HSP27. These findings suggest the potential use of DTNQ-Pro in combination chemotherapy for colon cancer.

Design and synthesis of spirotryprostatin-inspired diketopiperazine systems from prolyl spirooxoindolethiazolidine derivatives.

Based on the spirotryprostatin-A structure, we designed, synthesized, and evaluated different series of compounds belonging to the diketopiperazine structural class as potential cell cycle modulators and cytotoxic agents. Starting from the spirooxoindolthiazolidine scaffold, amide coupling with Pro derivatives and intramolecular cyclization reactions are suitable synthetic methods to generate chemically diverse diketopiperazine system, such as hexahydropyrrolo[1,2-a][1,3]thiazolo[3,2-d]pyrazine-5,10-dione (structure I), hexahydropyrrolo[1,2-a] [1,3]thiazolo[3,4-d]pyrazine-5,10-dione (structure II) and spiroindol-2-one[3,3']hexahydro-5,10H-pyrrolo[1,2-a][1,3]thiazolo[3,4-d]pyrazine-5,10-dione (structure III). Some of these compounds, especially those who belong to the series I and II, showed interesting cytotoxic activity.

Unprecedented synthesis of a novel amino quinone ring system via oxidative decarboxylation of quinone-based alpha,alpha-amino esters.

An unusual and efficient method for the synthesis of new quinone-based amine and its derivatives from the corresponding alpha,alpha-amino ester is described. The procedure involves the quinone-based system's oxidative decarboxylation via hydride transfer throughout basic hydrolysis. This synthetic method provides, with good yields, rapid access to new potentially cytotoxic quinones.

A new series of 1,3-dihidro-imidazo[1,5-c]thiazole-5,7-dione derivatives: synthesis and interaction with Abeta(25-35) amyloid peptide.

Deposition of senile plaques composed of fibrillar aggregates of Abeta-amyloid peptide is a characteristic hallmark of Alzheimer's disease. A widely employed approach in the study of anti-Alzheimer agents involves the identification of substances able to prevent amyloid aggregation, or to disaggregate the amyloid fibrils through a direct structural interaction with the soluble or aggregated forms of the peptide. Here, we report the synthesis of a set of 1,3-dihydro-3,6-disubstituted-imidazo[1,5-c]thiazole-5,7-dione derivatives supporting different alkyl, aryl and alkylamine side chains. The ability of these compounds to interact with the Abeta(25-35) peptide was evaluated using circular dichroism, nuclear magnetic resonance and thioflavin fluorescence spectroscopy. A molecular model for Abeta(25-35)-ligand interactions was calculated by molecular docking procedures. Our data show that the ability of the synthesized compounds to modify the structural behaviour of Abeta(25-35) varies as a function of the overall structural features of the ligands rather contributions from specific individual substituents.

Spiro[(dihydropyrazin-2,5-dione)-6,3'-(2',3'-dihydrothieno[2,3-b]naphtho-4',9'-dione)]-based cytotoxic agents: structure-activity relationship studies on the substituent at N4-position of the diketopiperazine domain.

Analogues of the previously reported potent cytotoxic spiro[(dihydropyrazine-2,5-dione)-6,3'-(2',3'-dihydrothieno[2,3-b]naphtho-4',9'-dione)] derivatives (3, 3') were prepared to explore new structural requirements at the diketopiperazine domain for the cytotoxic activity. The in vitro activity was evaluated against the MCF-7 human breast carcinoma and SW 620 human colon carcinoma cell lines. The 4-[(2-N, N-dimethyl)amino]ethyl (6i), and the 4-(2-pyrrolydin)ethyl (6l) derivatives emerged as the most potent compounds of this series, with a cytotoxic activity comparable to that of doxorubicin. These compounds, in both racemic and pure enantiomeric forms, showed also a high efficacy in cell lines resistant to doxorubicin (MCF-7/Dx) and in cell lines that were highly resistant to treatment with doxorubicin, such as HEK-293 (kidney), M-14 (melanoma), and HeLa (cervical adenocarcinoma) human cell lines. In addition, the effects on growth and cell cycle progression in CaCo-2 cell line (colon adenocarcinoma) and DNA-binding properties were investigated.