Enantioselective synthesis of dihydro-1H-benzindoles.

The first examples of dihydro-1H-benzindoles by enantioselective γ-lactamization reaction of naphthyl sulfilimines with trichloroacetyl chloride in the presence of ZnCu as catalyst (≥98:2 er and 65-80% yields) are described. Products are obtained by [3,3]-sigmatropic rearrangement of the azasulfonium enolate or followed by a second allylic rearrangement that transfers chirality. The absolute stereochemistry was confirmed by X-ray crystallography, which provides support for the mechanisms proposed.

Allylic thiocyanates as a new class of antitubercular agents.

TB is a global public health emergency in which new drugs are desperately needed. Herein we report on the synthesis of a diverse panel of 41 aryl allylic azides, thiocyanates, isothiouronium salts, and N,N'-diacetylisothioureas that were evaluated for their in vitro activity against replicating and non-replicating Mycobacterium tuberculosis (Mtb) H(37)Rv and toxicity to VERO cells. We found a selective group of new and promising compounds having good (micromolar) to excellent (sub-micromolar) potency against replicating Mtb H(37)Rv. Allylic thiocyanates bearing halophenyl (halo=2-Br, 4-Br, 4-Cl, 4-F), 4-methylphenyl and 2-naphthyl moieties were the most active as antitubercular agents. In particular, the 2-bromophenyl-substituted thiocyanate showed MIC=0.25 µM against replicating Mtb, MIC=8.0 µM against non-replicating Mtb and IC(50)=32 µM in the VERO cellular toxicity assay.

Antimicrobial and Toxicity Evaluation of Imidazolium-Based Dicationic Ionic Liquids with Dicarboxylate Anions.

Imidazolium-based dicationic ILs (DILs) presenting antimicrobial activity and relatively low toxicity are highly desirable and are envisioned for use in live tissue to prevent bacterial or fungal infections. In this context, we present here DILs with dicarboxylate anions [Cn(MIM)2[Cn(MIM)2][CO2-(CH2)mCO2], in which n = 4, 6, 8, and 10, and m = 0, 1, 2, 3, 4, and 5. The results showed that DILs with an alkyl chain spacer of ten carbons were active against yeasts and the bacterial strains tested. However, most of the DILs were cytotoxic and toxic at 1 mM. By contrast, DILs with alkyl chains possessing less than ten carbons were active against some specific Candidas and bacteria (mainly S. aureus), and they showed moderate cytotoxicity. The best activity against Gram-positive bacteria was observed for [C4(MIM)2][Pim] toward MRSA. For the DILs described herein, their level of toxicity against C. elegans was lower than that of most of the mono- and dicationic IL analogs with other anions. Our results showed that the presence of carboxylate anions reduces the toxicity of DILs compared to DILs containing halide anions, which is particularly significant to the means of designing biologically active compounds in antimicrobial formulations.

Structure-based design of δ-lactones for new antifungal drug development: susceptibility, mechanism of action, and toxicity.

Dermatophytes are the etiological agents of cutaneous mycoses, including the prevalent nail infections and athlete's foot. Candida spp. are opportunistic and emerging pathogens, causing superficial to deeper infections related to high mortality rates. As a consequence of prolonged application of antifungal drugs, the treatment failures combined with multidrug-resistance have become a serious problem in clinical practice. Therefore, novel alternative antifungals are required urgently. δ-Lactones have attracted great interest owing to their wide range of biological activity. This article describes the antifungal activity of synthetic δ-lactones against yeasts of the genus Candida spp. and dermatophytes (through the broth microdilution method), discusses the pathways by which the compounds exert this action (toward the fungal cell wall and/or membrane), and evaluates the toxicity to human leukocytes and chorioallantoic membrane (by the hen's egg test-chorioallantoic membrane). Two of the compounds in the series presented broader spectrum of antifungal activity, including against resistant fungal species. The mechanism of action was related to damage in the fungal cell wall and membrane, with specific target action dependent on the type of substituent present in the δ-lactone structure. The damage in the fungal cell was corroborated by electron microscopy images, which evidenced lysed and completely altered cells after in vitro treatment with δ-lactones. Toxicity was dose dependent for the viability of human leukocytes, but none of the compounds was mutagenic, genotoxic, or membrane irritant when evaluated at higher concentrations than MIC. In this way, δ-lactones constitute a class with excellent perspectives regarding their potential applications as antifungals.

Metal-free artificial nucleases based on simple oxime and hydroxylamine scaffolds.

Hydrolysis of DNA is of increasing importance in biotechnology and medicine. In this Letter, we present the DNA-cleavage potential of metal-free hydroxylamines and oximes as new members of nucleic acid cleavage agents.

Crystal structure of 5-O-benzoyl-2,3-O-iso-propyl-idene-d-ribono-1,4-lactone.

In the title compound, C15H16O6, obtained from the acyl-ation reaction between 2,3-O-iso-propyl-idene-d-ribono-1,4-lactone and benzoyl chloride, the known absolute configuration for the lactone moiety of the ester substituent has been confirmed. The five-membered rings of the bicyclic lactone-dioxolane moiety both show envelope conformations and form a dihedral angle of 19.82 (7)° between the lactone ring and the benzene ring. In the crystal, mol-ecules of the acyl-ated sugar are linked by very weak inter-molecular C-H⋯O inter-actions, forming a three-dimensional network.

Crystal structure and absolute configuration of (3aR,3'aR,7aS,7'aS)-2,2,2',2'-tetra-methyl-3a,6,7,7a,3'a,6',7',7'a-octa-hydro-4,4'-bi[1,3-benzodioxol-yl], obtained from a Pd-catalyzed homocoupling reaction.

The absolute configuration, i.e. (3aR,3'aR,7aS,7'aS), of the title compound, C18H26O4, synthesized via a palladium-catalyzed homocoupling reaction, was determined on the basis of the synthetic pathway and was confirmed by X-ray diffraction. The homocoupled mol-ecule is formed by two chemically identical moieties built up from two five- and six-membered fused rings. The supra-molecular assembly is controlled mainly by C-H⋯O inter-actions that lead to the formation of hydrogen-bonded chains of mol-ecules along the [001] direction, while weak dipolar inter-actions and van der Waals forces hold the chains together in the crystal structure.

Arginylglycylaspartic Acid-Surface-Functionalized Doxorubicin-Loaded Lipid-Core Nanocapsules as a Strategy to Target Alpha(V) Beta(3) Integrin Expressed on Tumor Cells.

Doxorubicin (Dox) clinical use is limited by dose-related cardiomyopathy, becoming more prevalent with increasing cumulative doses. Previously, we developed Dox-loaded lipid-core nanocapsules (Dox-LNC) and, in this study, we hypothesized that self-assembling and interfacial reactions could be used to obtain arginylglycylaspartic acid (RGD)-surface-functionalized-Dox-LNC, which could target tumoral cells overexpressing αvß3 integrin. Human breast adenocarcinoma cell line (MCF-7) and human glioblastoma astrocytoma (U87MG) expressing different levels of αvß3 integrin were studied. RGD-functionalized Dox-LNC were prepared with Dox at 100 and 500 mg·mL-1 (RGD-MCMN (Dox100) and RGD-MCMN (Dox500)). Blank formulation (RGD-MCMN) had z-average diameter of 162 ± 6 nm, polydispersity index of 0.11 ± 0.04, zeta potential of +13.2 ± 1.9 mV and (6.2 ± 1.1) × 1011 particles mL-1, while RGD-MCMN (Dox100) and RGD-MCMN (Dox500) showed respectively 146 ± 20 and 215 ± 25 nm, 0.10 ± 0.01 and 0.09 ± 0.03, +13.8 ± 2.3 and +16.4 ± 1.5 mV and (6.9 ± 0.6) × 1011 and (6.1 ± 1.0) × 1011 particles mL-1. RGD complexation was 7.73 × 104 molecules per nanocapsule and Dox loading were 1.51 × 104 and 7.64 × 104 molecules per nanocapsule, respectively. RGD-functionalized nanocapsules had an improved uptake capacity by U87MG cells. Pareto chart showed that the cell viability was mainly affected by the Dox concentration and the period of treatment in both MCF-7 and U87MG. The influence of RGD-functionalization on cell viability was a determinant factor exclusively to U87MG.

Crystal structure of 4-methyl-N-{(E)-meth-yl[(3aR,8aS)-2-oxo-3,3a,8,8a-tetra-hydro-2H-indeno-[1,2-d][1,3]oxazol-3-yl]-λ(4)-sulfanyl-idene}benzene-sulfonamide.

The formulation that the title compound, C18H18N2O4S2, adopts is a zwitterionic core with the charge separated to the sulfilimine S and N atoms and is supported by the two different S-N bond distances about the sulfinimine N atom [1.594 (2) and 1.631 (2) Å, respectively] that are typical for such bonds. The notably unusual bond is S-N(oxazolidinone) [1.692 (2) Å] that is longer than a typical S-N bond [1.603 (18) Å, Mogul analysis; Macrae et al. (2008 ▸). J. Appl. Cryst. 41, 466-470]. The bond-angle sum about sulfilimine sulfur (308.35°) reflects the trigonal-pyramidal geometry of this atom. Two of the angles are less than 100°. Despite the pyramidalization of this sulfur, there are no significant inter-molecular inter-actions, beyond usual van der Waals contacts, in the crystal packing.

Tamoxifen use and endometrial lesions: hysteroscopic, histological, and immunohistochemical findings in postmenopausal women with breast cancer.

OBJECTIVE: To evaluate immunohistochemical, hysteroscopic, and histological findings in postmenopausal women taking tamoxifen for breast cancer. METHODS: Forty postmenopausal women taking 20 mg/day tamoxifen for breast cancer underwent hysteroscopy and endometrial biopsy from January 2000 to December 2003. Medical records and paraffin blocks were analyzed retrospectively, and Ki-67, estrogen receptors (ERs), and progesterone receptors were measured using an immunohistochemical technique. RESULTS: The mean +/- SD age of the women was 59 +/- 14 years at hysteroscopy (95% CI, 54.2-63.7) and 45.1 +/- 7 years at menopause (95% CI, 42.6-47.6). Mean +/- SD duration of tamoxifen therapy was 27.3 +/- 16.5 months (95% CI, 22.0-32.5). Hysteroscopies were performed because of abnormal sonographic findings in 60% of the women and postmenopausal bleeding in 40%. The most common hysteroscopic and histological findings were endometrial polyps (32.5%) and atrophic endometria (22.5%). Immunohistochemistry showed that 85% of the women were progesterone receptor positive, 75% were ER positive, and 50% were Ki-67 positive. Endometrial polyps and polyps associated with atrophic endometrium were ER positive (P = 0.019). Results that were ER negative were more frequent in atrophic endometria (P = 0.01). The longer the time since menopause, the lower the Ki-67 expression in the endometrium was (P = 0.03). Ki-67 expression was greater in the endometrium of younger postmenopausal women (P = 0.01). CONCLUSIONS: The expression of steroid receptors in the endometrium was high in our series. All cases of endometrial polyps were ER positive. Estrogen receptors may play a major role in the development of endometrial polyps in postmenopausal women taking tamoxifen. Although most histological findings were benign, 22.5% were atrophic.

Biópsia por punçäo: um avanço diagnóstico em mastologia / Needle-core biopsy: an improvement in the diagnosis of suspicious breast lesions

Säo revisados os diversos aspectos do uso da biópsia por punçäo dos nódulos mamários, sua técnica, suas possibilidades quanto a dosagem de receptores hormonais e análise da ploidia de DNA, através da citometria de fluxo, assim como sua especificidade e sensibilidade. Com base na sensibilidade de 95,2 por cento com ausência de falso positivo, em 500 casos do Serviço de Oncologia Ginecológica e Mamária da Santa Casa de Porto Alegre, é sugerida a integraçäo do exame na rotina diagnóstica dos casos suspeitos de câncer de mama, com vistas a reduçäo de custos e de tempo dos profissionais envolvidos, sem afetar a segurança semiológica

Câncer de endométrio: condutas diagnósticas e terapêuticas / Adenocarcinoma of endometrium: diagnostic and therapeutic procedures

As condutas adotadas no Serviço de Ginecologia da Santa Casa de Porto Alegre no procedimento diagnóstico e na orientaçäo terapêutica do câncer de endométrio säo descritas. É enfatizado o valor da histerescopia no diagnóstico preciso do câncer de endométrio e discutidas as opçöes de tratamento cirúrgico

Câncer de colo uterino: condutas diagnósticas e terapêuticas / Cervical cancer: diagnosis and therapeutics

A conduta no diagnóstico e no tratamento das neoplasias intraepiteliais cervicais e do câncer de colo uterino adotadas no Serviço de Ginecologia da Santa Casa é descrita. O manejo dos meios diagnósticos e das opçöes terapêuticas é avaliado

Repercussöes psicossociais em mulheres acometidas por câncer de mama / Psychosocial repercussions among women with breast cancer

O objetivo da pesquisa foi identificar repercussöes psicossociais em 26 mulheres acometidas de câncer de mama, durante quatro momentos de evoluçäo do tratamento: pré-operatório e 2, 4 e 6 meses após a cirurgia-mastectomia radical ou cirurgia conservadora. Os instrumentos utilizados foram entrevistas para examinar os aspectos sócio-demográficos, clínico ginecológicos, perfil psicossocial e repercussöes decorrentes do tratamento cirúrgico e terapias adjuvantes e escalas de ansiedade (Zung) e de depressäo (Zung e MADRS), para avaliar a evoluçäo dos sintomas psiquiátricos. Os achados, tratados quantitativa e qualitativamente, revelam uma série de elementos muito úteis para a compreensäo e manejo da paciente acometida por câncer da mama. É baixa a incidência de auto-exame de mamas. Há queixas do recebimento de poucas ou imprecisas informaçöes tanto no pré como no pós-operatório. Apesar de vivências de alteraçöes da imagem corporal, primordial é a questäo da sobrevivência e, em segundo lugar, o tema da mutilaçäo. Questöes acerca de sexualidade e conjugalidade se mostraram prejudicadas pelo fato de que a maior parte das pacientes declaravam estar sem companheiro. Sintomas de ansiedade e depressäo, a nível reacional, säo encontrados tanto nos resultados das escalas, como nos dados qualitativos das entrevistas

Conduta diagnóstica e terapêutica em tumores de mama normas do Serviço de Ginecologia da ISCMPA e do Serviço de Oncologia Ginecológica e Mamária do Hospital Santa Rita / Principles of diagnosis and therapeutic procedures in breast cancer

Säo relatados os princípios de orientaçäo diagnóstica e terapêutica em câncer de mama adotados no serviço. A semiologia é baseada no exame clínico, na mamografia, na ultra-sonografia mamária e na biópsia por punçäo. As indicaçöes de cirurgia conservadora e de mastectomia radical säo discutidas, assim como a conduta em situaçöes especiais e a terapêutica adjuvante após o tratamento cirúrgico