From Cyclopropene to Housane Derivatives Via Intramolecular Cyclopropanation.

The synthesis of housanes derivatives from cyclopropenes is described. Under rhodium(II) catalysis, cyclopropenylvinyl carbinols can regioselectively generate a carbene intermediate which undergo an intramolecular cyclopropanation to form a housane, a skeleton with similar ring strain as the cyclopropene precursor. The procedure shows a remarkable broad scope and efficiency. Moreover, the method served to prepare man-made housane-containing terpene derivatives, which are not accessible by Nature.

Human Triosephosphate Isomerase Is a Potential Target in Cancer Due to Commonly Occurring Post-Translational Modifications.

Cancer involves a series of diseases where cellular growth is not controlled. Cancer is a leading cause of death worldwide, and the burden of cancer incidence and mortality is rapidly growing, mainly in developing countries. Many drugs are currently used, from chemotherapeutic agents to immunotherapy, among others, along with organ transplantation. Treatments can cause severe side effects, including remission and progression of the disease with serious consequences. Increased glycolytic activity is characteristic of cancer cells. Triosephosphate isomerase is essential for net ATP production in the glycolytic pathway. Notably, some post-translational events have been described that occur in human triosephosphate isomerase in which functional and structural alterations are provoked. This is considered a window of opportunity, given the differences that may exist between cancer cells and their counterpart in normal cells concerning the glycolytic enzymes. Here, we provide elements that bring out the potential of triosephosphate isomerase, under post-translational modifications, to be considered an efficacious target for treating cancer.

The Giardial Arginine Deiminase Participates in Giardia-Host Immunomodulation in a Structure-Dependent Fashion via Toll-like Receptors.

Beyond the problem in public health that protist-generated diseases represent, understanding the variety of mechanisms used by these parasites to interact with the human immune system is of biological and medical relevance. Giardia lamblia is an early divergent eukaryotic microorganism showing remarkable pathogenic strategies for evading the immune system of vertebrates. Among various multifunctional proteins in Giardia, arginine deiminase is considered an enzyme that plays multiple regulatory roles during the life cycle of this parasite. One of its most important roles is the crosstalk between the parasite and host. Such a molecular "chat" is mediated in human cells by membrane receptors called Toll-like receptors (TLRs). Here, we studied the importance of the 3D structure of giardial arginine deiminase (GlADI) to immunomodulate the human immune response through TLRs. We demonstrated the direct effect of GlADI on human TLR signaling. We predicted its mode of interaction with TLRs two and four by using the AlphaFold-predicted structure of GlADI and molecular docking. Furthermore, we showed that the immunomodulatory capacity of this virulent factor of Giardia depends on the maintenance of its 3D structure. Finally, we also showed the influence of this enzyme to exert specific responses on infant-like dendritic cells.

Multilevel Approach for the Treatment of Giardiasis by Targeting Arginine Deiminase.

Giardiasis represents a latent problem in public health due to the exceptionally pathogenic strategies of the parasite Giardia lamblia for evading the human immune system. Strains resistant to first-line drugs are also a challenge. Therefore, new antigiardial therapies are urgently needed. Here, we tested giardial arginine deiminase (GlADI) as a target against giardiasis. GlADI belongs to an essential pathway in Giardia for the synthesis of ATP, which is absent in humans. In silico docking with six thiol-reactive compounds was performed; four of which are approved drugs for humans. Recombinant GlADI was used in enzyme inhibition assays, and computational in silico predictions and spectroscopic studies were applied to follow the enzyme's structural disturbance and identify possible effective drugs. Inhibition by modification of cysteines was corroborated using Ellman's method. The efficacy of these drugs on parasite viability was assayed on Giardia trophozoites, along with the inhibition of the endogenous GlADI. The most potent drug against GlADI was assayed on Giardia encystment. The tested drugs inhibited the recombinant GlADI by modifying its cysteines and, potentially, by altering its 3D structure. Only rabeprazole and omeprazole decreased trophozoite survival by inhibiting endogenous GlADI, while rabeprazole also decreased the Giardia encystment rate. These findings demonstrate the potential of GlADI as a target against giardiasis.

Gold-Catalyzed Reaction of Propargyl Esters and Alkynylsilanes: Synthesis of Vinylallene Derivatives through a Twofold 1,2-Rearrangement.

The reaction of propargyl esters with alkynylsilanes under gold catalysis provides vinylallene derivatives through consecutive [1,2]-acyloxy/[1,2]-silyl rearrangements. Good yields, full atom-economy, broad substrate scope, easy scale-up and low catalyst loadings are salient features of this novel transformation. Density Functional Theory (DFT) calculations suggest a reaction mechanism involving initial [1,2]-acyloxy rearrangement to generate a gold vinylcarbene intermediate which upon regioselective attack of the alkynylsilane affords a vinyl cation which undergoes a type II-dyotropic rearrangement involving the silyl group and the metal fragment. Preliminary results on the enantioselective version of this transformation are also disclosed.

Gold-Catalyzed [3+2] Carbocycloaddition Reaction of Pinacol Alkenylboronates: Stereospecific Synthesis of Boryl-Functionalized Cyclopentene Derivatives.

Gold-catalysis has enabled new synthetic opportunities in the chemistry of vinyldiazo compounds. Herein, we report the gold-catalyzed reaction of stabilized vinyldiazo compounds with pinacol alkenylboronates to provide boryl-functionalized cyclopentene derivatives through a formal [3+2] carbocycloaddition reaction, a very unusual pathway in alkenylboronate chemistry. This reaction proceeds with high regio- and stereoselectivity. The synthetic usefulness of the resulting borylated cyclopentene derivatives toward the synthesis of densely functionalized cyclopentanoids is also demonstrated.

Echocardiographic parameters, speckle tracking, and brain natriuretic peptide levels as indicators of progression of indeterminate stage to Chagas cardiomyopathy.

BACKGROUND: Chronic Chagas cardiomyopathy (CCM) is characterized by a unique type of cardiac involvement. Few studies have characterized echocardiographic (Echo) transitions from the indeterminate Chagas disease (ChD) form to CCM. The objective of this study was to identify the best cutoffs in multiple Echo parameters, speckle tracking, and N-terminal pro B-type natriuretic peptide (NT-proBNP) to distinguish patients without CCM (stage A) vs patients with myocardial involvement (stages B, C, or D). METHODS: Cross-sectional study conducted in 273 consecutive patients with different CCM stages. Echo parameters, NT-proBNP, and other clinical variables were measured. Logistic regression models (dichotomized in stage A versus B, C, and D) adjusted for age, sex, body mass index, and NT-proBNP were performed. RESULTS: Left ventricular global longitudinal strain (LV-GLS), mitral flow E velocity, LV mass index, and NT-proBNP identified early changes that differentiated stages A vs B, C, and D. The LV-GLS with a cutoff -20.5% showed the highest performance (AUC 92.99%; accuracy 84.56% and negative predictive value (NPV) 88.82%), which improved when it was additionally adjusted by NT-proBNP with a cutoff -20.0% (AUC 94.30%; accuracy 88.42% and NPV 93.55%). CONCLUSIONS: Our findings suggest that Echo parameters and NT-proBNP may be used as diagnostic variables in detecting the onset of myocardial alterations in patients with the indeterminate stage of ChD. LV-GLS was the more accurate measurement regarding stage A differentiation from the stages B, C, and D. Prospective longitudinal studies are needed to validate these findings.

Copper(i)-carbenes as key intermediates in the [3 + 2]-cyclization of pyridine derivatives with alkenyldiazoacetates: a computational study.

This work reports a computational study of the copper(i)-catalyzed regioselective synthesis of indolizine derivatives through the [3 + 2]-cyclization reaction of vinyldiazo acetates and pyridine derivatives. This reaction is predicted to proceed via a multi-step process with the initial decomposition of the diazo function and generation of an electrophilic copper(i) carbene intermediate. Subsequent attack of the pyridine derivative at the vinylogous position of the carbene would generate a vinylcuprate intermediate that would evolve to the final products through a sequence involving cyclization, reductive elimination, metal decoordination and final oxidative aromatization. According to our calculations, an alternative pathway involving the initial activation of the pyridine seems unlikely. These theoretical results could pave the way for further developments in vinyldiazo chemistry.

Synthesis of 1,2-divinylcyclopropanes by metal-catalyzed cyclopropanation of 1,3-dienes with cyclopropenes as vinyl carbene precursors.

The synthesis of 1,2-divinylcyclopropanes by the reaction of cyclopropenes with 1,3-dienes is reported. The process relies on the ability of ZnCl2 or [Rh2(OAc)4] to generate metal-vinyl carbene intermediates from cyclopropenes, which effect cyclopropanation of 1,3-dienes. Most of the reactions proceeded in reasonable yields while the diastereoselectivity strongly depends on the structure of the diene. An example of an intramolecular process as well as the use of furan and 1,4-cyclohexadiene as dienes are also reported.

Is Seasonal Households' Consumption Good for the Nexus Carbon/Water Footprint? The Spanish Fruits and Vegetables Case.

Proximity and in-season consumption criteria have been suggested as solutions for fruits and vegetables consumers to drive the economy to a more sustainable development. Using a new concept, seasonal avoided footprint by imports, we disentangle the role of period and country of origin. Although, as a general rule, consumers could reduce the footprint by choosing domestic produce, this is not always the case. Due to the high efficiency of Spanish domestic production in terms of both CO2e and water use (except for scarce water), imports from some regions, like Africa (green beans, peppers, tomatoes, bananas, strawberries, oranges), contribute to significantly increasing both water and carbon impacts. However, a monthly basis analysis shows unsustainable hotspots for domestic production. Importing from France (apples, potatoes) or Portugal (tomatoes, strawberries) reduces both footprints, so Spanish local consumption would be bad for the environment. Hotspots are mainly concentrated in scarce water and, especially, for out-of-season vegetables during 11 months a year (savings up to 389%), nine months for out-of-season fruits, and five months for in-season fruits. The results suggest the difficulty to generalize an easy environmental recommendation based on buying local fruits and vegetables: consumption must be analyzed on monthly/seasonal, product, and country bases.

Trapping para-Quinone Methide Intermediates with Ferrocene: Synthesis and Preliminary Biological Evaluation of New Phenol-Ferrocene Conjugates.

The reaction of para-hydroxybenzyl alcohols with ferrocene in the presence of a catalytic amount of InCl3 provided ferrocenyl phenol derivatives, an interesting class of organometallic compounds with potential applications in medicinal chemistry. This transformation exhibited a reasonable substrate scope delivering the desired products in synthetically useful yields. Evidence of involvement of a para-quinone methide intermediate in this coupling process was also provided. Preliminary biological evaluation demonstrated that some of the ferrocene derivatives available by this methodology exhibit significant cytotoxicity against several cancer cell lines with IC50 values within the range of 1.07⁻4.89 µM.

Body Mass Index and Surgical Outcome in a Puerto Rican Population.

OBJECTIVE: To determine the impact of body mass index (BMI) on postoperative morbidity and 30-day mortality in the population served by the University of Puerto Rico (UPR)-affiliated hospitals. METHODS: We reviewed the surgical data entered into the UPR General Surgery Department database from January 1, 2014, through June 30, 2016. This database collects patient and procedural information from the UPR-affiliated hospitals. We compared the postoperative morbidity and 30-day mortality rates of 5 different BMI groups: underweight (<18.5 kg/m2), normal weight (18.5-24.9 kg/m2), overweight (25.0-29.9 kg/m2), obese, classes I and II (30-39.9 kg/m2), and morbidly obese (>=40 kg/m2). Multivariable regression analyses, adjusted for age, gender, and surgery type, were used to evaluate the risks for each BMI category. RESULTS: Information on 9,856 patients was reviewed. The mean age of the sample population was 52 (±20) years; 57% were women and 43% were men. The postoperative morbidity and 30-day mortality rates of the underweight group were significantly higher than those of the normal-weight group (6.1% vs. 3.1% and 2.1% vs. 0.5%, respectively; p<0.001). The morbidly obese also had significantly higher (p<0.001) postoperative morbidity (5.3% vs. 2.1%) and 30-day mortality rates (2.7% vs. 0.5%) compared to normal-weight patients. The odds of 30-day mortality were significantly higher for the underweight (odds ratio [OR], 5.64; 95% confidence interval [CI], 2.47-12.92) and morbidly obese patients (OR, 7.23; 95% CI, 3.01-17.39). The overweight patients had no increased risk, and the obese patients had a slight increase in morbidity (OR, 1.54; 95% CI, 1.08-2.21) but no significant increase in 30-day mortality (p>0.05). CONCLUSION: Patients at the extremes of the BMI have more postoperative complications and higher 30-day mortality rates than do patients with mid-range scores.

Synthesis of Bifunctional Allylic Compounds by Using Cyclopropenes as Functionalized Allyl Equivalents.

The synthesis of uncommon bifunctional allylic derivatives bearing a silane and an alcohol within the same allylic framework is reported. This method relies on the coupling of hydrosilanes with substituted and functionalized cyclopropenes, which deliver the allyl fragment. Rhodium(II) catalysts provide regioselective access to vinyl carbene intermediates, which easily undergo Si-H bond insertions. The transformation occurs with complete atom economy and shows a remarkably broad scope, including a intramolecular version for the synthesis of cyclic O-Si-linked compounds as well as the synthesis of the corresponding allyl amines.

Gold-Catalyzed Intermolecular Formal Insertion of Aryldiazo Esters into Cp-H Bonds of Iron and Ruthenium Metallocenes.

The reaction of ferrocene and ruthenocene with aryldiazo acetates in the presence of gold catalysts produced new functionalized metallocenes resulting from a C-H bond functionalization process. This process is believed to proceed through initial decomposition of the diazo component and formation of an electrophilic gold-carbene intermediate, which is subsequently involved in an electrophilic aromatic substitution. The gold-catalyzed functionalization of ruthenocene exhibited a broad scope and a notable functional-group tolerance. Interestingly, the functionalized ferrocene derivatives were found to react with molecular oxygen to yield α-aryl-α-ferrocenyl-α-hydroxyacetates. Adsorption on silica gel was found to be essential for this dioxygen activation/C(sp3 )-H bond functionalization sequence. The methodologies reported herein provide a simple and efficient approach to functionalized metallocene derivatives that are difficult to access through conventional organic functional group transformations.

Zinc-Catalyzed Synthesis of Conjugated Dienoates through Unusual Cross-Couplings of Zinc Carbenes with Diazo Compounds.

Zinc-catalyzed selective cross-coupling of two carbene sources, such as vinyl diazo compounds and enynones, enabled the synthesis of conjugated dienoate derivatives. This reaction involved the unprecedented coupling of a zinc furyl carbene with vinyl diazo compounds through the γ-carbon. Alternatively, dienoates were also prepared by a commutative cross-coupling of zinc vinyl carbenes generated from cyclopropenes and simple diazo compounds.

Recent Developments in Coinage Metal Catalyzed Transformations of Stabilized Vinyldiazo Compounds: Beyond Carbenic Pathways.

Transition metal-catalyzed transformations of vinyldiazo compounds have become a versatile tool in organic synthesis. Although several transition metals have been investigated for this purpose, this field has been mainly dominated by dirhodium catalysts. Remarkable levels of chemo-, regio-, diastereo- and enantioselectivity have been reached in some of these rhodium-catalyzed transformations. In the last few years coinage metals have also emerged as useful catalysts in transformations involving vinyldiazo compounds. In some cases, highly efficient catalyst-dependent protocols arising from divergent mechanistic pathways have been reported. In this Personal Account, we aim to showcase recent advances in metal coinage catalyzed transformations of vinyldiazoacetates, an exciting field of research to which our group has actively contributed in the last few years.

Zinc-Catalyzed Synthesis of Allylsilanes by Si-H Bond Insertion of Vinyl Carbenoids Generated from Cyclopropenes.

Allylsilanes have long been recognized as valuable building blocks for organic synthesis. A zinc-catalyzed reaction of cyclopropenes and hydrosilanes provides a convenient route to these versatile unsaturated organosilanes. In this transformation, ZnBr2 serves as an efficient catalyst, allowing the generation of a zinc vinyl carbenoid intermediate, which is subsequently involved in a Si-H bond insertion. The process shows broad scope, and is amenable to substituted and functionalized cyclopropenes or the functionalization of polysiloxanes. Moreover, zinc-catalyzed carbene insertion into a Ge-H bond is reported for the first time.

Synthesis of Functionalized Cyclopentene Derivatives from Vinyldiazo Compounds and Vinylazides through Sequential Copper-Promoted [3+2] Cycloaddition/Azide Rearrangement.

The reaction of vinylazides with alkenyldiazo compounds in the presence of [Cu(CH3 CN)4 ][BF4 ] provided cyclopentene derivatives with retention of the azide functionality. This process likely involves a sequence comprising: 1) decomposition of the diazo component with generation of a copper alkenylcarbene species; 2) stepwise regioselective [3+2] cycloaddition; 3) allylic azide rearrangement. This method is compatible with a broad range of substrates. We also show that the azide-containing cycloadducts can be efficiently converted into the corresponding amine and triazole derivatives.

Changes of myoid and endothelial cells in the peritubular wall during contraction of the seminiferous tubule.

The wall of the seminiferous tubule in rodents consists of an inner layer of myoid cells covered by an outer layer of endothelial cells. Myoid cells are a type of smooth muscle cell containing α-actin filaments arranged in two independent layers that contract when stimulated by endothelin-1. The irregular surface relief of the tubular wall is often considered a hallmark of contraction induced by a variety of stimuli. We examine morphological changes of the rat seminiferous tubule wall during contraction by a combination of light, confocal, transmission and scanning electron microscopy. During ET-1-induced contraction, myoid cells changed from a flat to a conical shape, but their actin filaments remained in independent layers. As a consequence of myoid cell contraction, the basement membrane became wavy, orientation of collagen fibers in the extracellular matrix was altered and the endothelial cell layer became folded. To observe the basement of the myoid cell cone, the endothelial cell monolayer was removed by collagenase digestion prior to SEM study. In contracted tubules, it is possible to distinguish cell relief: myoid cells have large folds on the external surface oriented parallel to the tubular axis, whereas endothelial cells have numerous cytoplasmic projections facing the interstitium. The myoid cell cytoskeleton is unusual in that the actin filaments are arranged in two orthogonal layers, which adopt differing shapes during contraction with myoid cells becoming cone-shaped. This arrangement impacts on other components of the seminiferous tubule wall and affects the propulsion of the tubular contents to the rete testis.

Rab24 is required for normal cell division.

Rab24 is an atypical member of the Rab GTPase family whose distribution in interphase cells has been characterized; however, its function remains largely unknown. In this study, we have analyzed the distribution of Rab24 throughout cell division. We have observed that Rab24 was located at the mitotic spindle in metaphase, at the midbody during telophase and in the furrow during cytokinesis. We have also observed partial co-localization of Rab24 and tubulin and demonstrated its association to microtubules. Interestingly, more than 90% of transiently transfected HeLa cells with Rab24 presented abnormal nuclear connections (i.e., chromatin bridges). Furthermore, in CHO cells stably transfected with GFP-Rab24wt, we observed a large percentage of binucleated and multinucleated cells. In addition, these cells presented an extremely large size and multiple failures in mitosis, as aberrant spindle formation (metaphase), delayed chromosomes (telophase) and multiple cytokinesis. A marked increase in binucleated, multinucleated and multilobulated nucleus formation was observed in HeLa cells depleted of Rab24. We also present evidence that a fraction of Rab24 associates with microtubules. In addition, Rab24 knock down resulted in misalignment of chromosomes and abnormal spindle formation in metaphase leading to the appearance of delayed chromosomes during late telophase and failures in cytokinesis. Our findings suggest that an adequate level of Rab24 is necessary for normal cell division. In summary, Rab24 modulates several mitotic events, including chromosome segregation and cytokinesis, perhaps through the interaction with microtubules.