Reusando Modelos Conceituais : Linguagem e Compilador

TCC(graduação) - Universidade Federal de Santa Catarina. Centro Tecnológico. Ciências da Computação.Este relatório apresenta uma linguagem textual para modelagem con- ceitual (baseada em classes/associações da UML e em restrições da OCL) e um compilador que pode gerar código em qualquer linguagem ou tecnologia através de templates de texto extensíveis. A linguagem e o compilador permitem a especificação da informação gerenciada por sistemas de software cada vez mais distribuídos e em constante mu- dança. A partir de uma única fonte, a geração de código automática mantém as implementações consistentes com sua especificação atra- vés das diferentes plataformas e tecnologias. Além disso, na medida em que o horizonte tecnológico se expande, os templates textuais po- dem ser modificados para adotar novas tecnologias. Diferentemente de outras abordagens, tais como MDA e MPS, espera-se que o suporte fer- ramental acompanhando esta linguagem, juntamente com sua natureza textual, facilite a integração do desenvolvimento de software dirigido por modelos no fluxo de trabalho dos desenvolvedores de software

Utilizing Redox-Mediated Bergman Cyclization toward the Development of Dual-Action Metalloenediyne Therapeutics

Reaction of 2 equiv of 1,2-bis­((diphenyl­phosphino)­ethynyl)­benzene (dppeb, <b>1</b>) with Pt­(cod)­Cl₂ followed by treatment with N₂H₄ yields the reduced Pt(0) metalloenediyne, Pt­(dppeb)₂, <b>2</b>. This complex is stable to both air oxidation and metal-mediated Bergman cyclization under ambient conditions due to the nearly idealized tetrahedral geometry. Reaction of <b>2</b> with 1 equiv of I₂ in the presence of excess 1,4-cyclohexadiene (1,4-CHD) radical trap rapidly and near-quantitatively generates the <i>cis</i>-Bergman-cyclized, diiodo product <b>3</b> (³¹P: δ = 41 ppm, <i>J</i>_Pt–P = 3346 Hz) with concomitant loss of 1 equiv of uncyclized phosphine chelate (³¹P: δ = −33 ppm). In contrast, addition of 2 equiv of I₂ in the absence of additional radical trap instantaneously forms a metastable Pt­(dppeb)₂²⁺ intermediate species, <b>4</b>, that is characterized by δ = 51 ppm in the ³¹P NMR (<i>J</i>_Pt–P = 3171 Hz) and ν_CC = 2169 cm^–1 in the Raman profile, indicating that it is an uncyclized, bis-ligated complex. Over 24 h, <b>4</b> undergoes ligand exchange to form a neutral, square planar complex that spontaneously Bergman cyclizes at ambient temperature to give the crystalline product Pt­(dppnap-I₂)­I₂ (dppnap-I₂ = (1,4-diiodonaphthalene-2,3-diyl)­bis­(diphenylphosphine)), <b>5</b>, in 52% isolated yield. Computational analysis of the oxidation reaction proposes two plausible flattened tetrahedral structures for intermediate <b>4</b>: one where the phosphine core has migrated to a <i>trans</i>-spanning chelate geometry, and a second, higher energy structure (3.3 kcal/mol) with two <i>cis</i>-chelating phosphine ligands (41° dihedral angle) via a restricted alkyne-terminal starting point. While the energies are disparate, the common theme in both structures is the elongated Pt–P bond lengths (>2.4 Å), indicating that nucleophilic ligand substitution by I^– is on the reaction trajectory to the cyclized product <b>5</b>. The efficiency of the redox-mediated Bergman cyclization reaction of this stable Pt(0) metalloenediyne prodrug and resulting cisplatin-like byproduct represents an intriguing new strategy for potential dual-threat metalloenediyne therapeutics

Utilizing Redox-Mediated Bergman Cyclization toward the Development of Dual-Action Metalloenediyne Therapeutics

Reaction of 2 equiv of 1,2-bis­((diphenyl­phosphino)­ethynyl)­benzene (dppeb, <b>1</b>) with Pt­(cod)­Cl₂ followed by treatment with N₂H₄ yields the reduced Pt(0) metalloenediyne, Pt­(dppeb)₂, <b>2</b>. This complex is stable to both air oxidation and metal-mediated Bergman cyclization under ambient conditions due to the nearly idealized tetrahedral geometry. Reaction of <b>2</b> with 1 equiv of I₂ in the presence of excess 1,4-cyclohexadiene (1,4-CHD) radical trap rapidly and near-quantitatively generates the <i>cis</i>-Bergman-cyclized, diiodo product <b>3</b> (³¹P: δ = 41 ppm, <i>J</i>_Pt–P = 3346 Hz) with concomitant loss of 1 equiv of uncyclized phosphine chelate (³¹P: δ = −33 ppm). In contrast, addition of 2 equiv of I₂ in the absence of additional radical trap instantaneously forms a metastable Pt­(dppeb)₂²⁺ intermediate species, <b>4</b>, that is characterized by δ = 51 ppm in the ³¹P NMR (<i>J</i>_Pt–P = 3171 Hz) and ν_CC = 2169 cm^–1 in the Raman profile, indicating that it is an uncyclized, bis-ligated complex. Over 24 h, <b>4</b> undergoes ligand exchange to form a neutral, square planar complex that spontaneously Bergman cyclizes at ambient temperature to give the crystalline product Pt­(dppnap-I₂)­I₂ (dppnap-I₂ = (1,4-diiodonaphthalene-2,3-diyl)­bis­(diphenylphosphine)), <b>5</b>, in 52% isolated yield. Computational analysis of the oxidation reaction proposes two plausible flattened tetrahedral structures for intermediate <b>4</b>: one where the phosphine core has migrated to a <i>trans</i>-spanning chelate geometry, and a second, higher energy structure (3.3 kcal/mol) with two <i>cis</i>-chelating phosphine ligands (41° dihedral angle) via a restricted alkyne-terminal starting point. While the energies are disparate, the common theme in both structures is the elongated Pt–P bond lengths (>2.4 Å), indicating that nucleophilic ligand substitution by I^– is on the reaction trajectory to the cyclized product <b>5</b>. The efficiency of the redox-mediated Bergman cyclization reaction of this stable Pt(0) metalloenediyne prodrug and resulting cisplatin-like byproduct represents an intriguing new strategy for potential dual-threat metalloenediyne therapeutics

Expedient Synthesis of Furo[2,3<i>-d</i>][1,3]thiazinamines and Pyrano[2,3‑<i>d</i>][1,3]thiazinamines from Enones and Thiourea

Michael addition of thiourea to enones with subsequent intramolecular aminal ether formation provided easy access to furo­[2,3-<i>d</i>]­thiazinamines and pyrano­[2,3-<i>d</i>]­[1,3]­thiazin-2-amines. These amines served as versatile intermediates to a variety of beta-amyloid cleaving enzyme-1 (BACE1) inhibitors

Utilizing Redox-Mediated Bergman Cyclization toward the Development of Dual-Action Metalloenediyne Therapeutics

Reaction of 2 equiv of 1,2-bis­((diphenyl­phosphino)­ethynyl)­benzene (dppeb, <b>1</b>) with Pt­(cod)­Cl₂ followed by treatment with N₂H₄ yields the reduced Pt(0) metalloenediyne, Pt­(dppeb)₂, <b>2</b>. This complex is stable to both air oxidation and metal-mediated Bergman cyclization under ambient conditions due to the nearly idealized tetrahedral geometry. Reaction of <b>2</b> with 1 equiv of I₂ in the presence of excess 1,4-cyclohexadiene (1,4-CHD) radical trap rapidly and near-quantitatively generates the <i>cis</i>-Bergman-cyclized, diiodo product <b>3</b> (³¹P: δ = 41 ppm, <i>J</i>_Pt–P = 3346 Hz) with concomitant loss of 1 equiv of uncyclized phosphine chelate (³¹P: δ = −33 ppm). In contrast, addition of 2 equiv of I₂ in the absence of additional radical trap instantaneously forms a metastable Pt­(dppeb)₂²⁺ intermediate species, <b>4</b>, that is characterized by δ = 51 ppm in the ³¹P NMR (<i>J</i>_Pt–P = 3171 Hz) and ν_CC = 2169 cm^–1 in the Raman profile, indicating that it is an uncyclized, bis-ligated complex. Over 24 h, <b>4</b> undergoes ligand exchange to form a neutral, square planar complex that spontaneously Bergman cyclizes at ambient temperature to give the crystalline product Pt­(dppnap-I₂)­I₂ (dppnap-I₂ = (1,4-diiodonaphthalene-2,3-diyl)­bis­(diphenylphosphine)), <b>5</b>, in 52% isolated yield. Computational analysis of the oxidation reaction proposes two plausible flattened tetrahedral structures for intermediate <b>4</b>: one where the phosphine core has migrated to a <i>trans</i>-spanning chelate geometry, and a second, higher energy structure (3.3 kcal/mol) with two <i>cis</i>-chelating phosphine ligands (41° dihedral angle) via a restricted alkyne-terminal starting point. While the energies are disparate, the common theme in both structures is the elongated Pt–P bond lengths (>2.4 Å), indicating that nucleophilic ligand substitution by I^– is on the reaction trajectory to the cyclized product <b>5</b>. The efficiency of the redox-mediated Bergman cyclization reaction of this stable Pt(0) metalloenediyne prodrug and resulting cisplatin-like byproduct represents an intriguing new strategy for potential dual-threat metalloenediyne therapeutics

Vitamin D-binding protein in cervicovaginal fluid as a non-invasive predictor of intra-amniotic infection and impending preterm delivery in women with preterm labor or preterm premature rupture of membranes

<div><p>Objective</p><p>To determine whether vitamin D-binding protein (VDBP) in cervicovaginal fluid (CVF) is independently predictive of intra-amniotic infection and imminent spontaneous preterm delivery (SPTD, delivery within 48 hours) in women with preterm labor with intact membranes (PTL) or preterm premature rupture of membranes (PPROM).</p><p>Method</p><p>This was a single-center retrospective cohort study. CVF samples for VDBP assays were obtained along with serum C-reactive protein (CRP) levels immediately after amniocentesis in consecutive women with PTL (n = 148) or PPROM (n = 103) between 23.0 and 34.0 weeks of gestation. VDBP levels in CVF were determined by enzyme-linked immunosorbent assay kits. The primary outcome measures were intra-amniotic infection [defined as positive amniotic fluid (AF) culture] and SPTD within 48 hours after sampling.</p><p>Results</p><p>In the multivariable analysis, elevated VDBP levels in CVF samples of PTL women were significantly associated with intra-amniotic infection and imminent preterm delivery, even after adjusting for potential confounders (e.g., gestational age at sampling, parity, and serum CRP). However, these relationships were not found in women with PPROM. In women with PTL, the areas under receiver operating characteristic curves of CVF VDBP level for predicting intra-amniotic infection and imminent preterm delivery were 0.66 and 0.71, with cut-off values of 1.76 μg/mL (sensitivity of 64.3% and specificity of 78.4%) and 1.37 μg/mL (sensitivity of 65.4% and specificity of 72.6%), respectively. The CVF VDBP levels were significantly higher in women with PPROM than in those with PTL.</p><p>Conclusions</p><p>VDBP in the CVF independently predicts intra-amniotic infection and imminent preterm delivery in women with PTL, whereas in women with PPROM, an elevated VDBP level in CVF is not associated with increased risks of these two outcome variables.</p></div

An Enantioselective Total Synthesis of (+)-Duocarmycin SA

An efficient, concise enantioselective total synthesis of the potent antitumor antibiotic (+)-duocarmycin SA is described. The invented route is based on a disconnection strategy that was devised to facilitate rapid and efficient synthesis of key core compounds to enable preclinical structure–activity relationship investigations. The key tricycle core was constructed with a highly enantioselective indole hydrogenation to set the stereocenter and a subsequent hitherto unexplored vicarious, nucleophilic-substitution/cyclization sequence to effectively forge a final indole ring. Additionally, the development of a stable sulfonamide protecting group capable of mild chemoselective cleavage greatly enhanced sequence yield and throughput. An understanding of key reaction parameters ensured a robust, reproducible sequence easily executable on decagram scales to this highly promising class of compounds

Kaplan-Meier survival estimates of the sampling-to-delivery interval according to the levels of vitamin D-binding protein (VDBP) in the cervicovaginal fluid of women with preterm labor and intact membranes (using 1.37 μg/mL as a cut-off) (median, 9.91 days [95% confidence interval (CI), 5.17–14.65] vs. 45.87 days [95% CI, 36.84–54.90]; <i>P</i> = 0.003).

<p>Kaplan-Meier survival estimates of the sampling-to-delivery interval according to the levels of vitamin D-binding protein (VDBP) in the cervicovaginal fluid of women with preterm labor and intact membranes (using 1.37 μg/mL as a cut-off) (median, 9.91 days [95% confidence interval (CI), 5.17–14.65] vs. 45.87 days [95% CI, 36.84–54.90]; <i>P</i> = 0.003).</p

Clinical characteristics of the study population according to the status of the fetal membrane (intact or ruptured membranes).

<p>Clinical characteristics of the study population according to the status of the fetal membrane (intact or ruptured membranes).</p

Characteristics of the study population according to amniotic fluid culture results.

<p>Characteristics of the study population according to amniotic fluid culture results.</p