Activación de aldehídos a,b-insaturados mediante aminocatálisis en procesos enantioselectivos. Cicloadiciones (3+2) y reacciones en cascada Michael/Henry

During the research that it is summarized in the present memory, the activation of enals via iminium ion catalysis in different transformations has been studied. Firstly, a 1,3-dipolar cycloaddition between stable azomethine ylides and a,b-unsaturated aldehydes catalyzed by a chiral imidazolidinone derivative has been optimized. Employing this methodology we have synthesized a large range of densely substituted pyrroloisoquinolines and pyrrolophthalazines with good yields and high values of diastereo- and enantioselectivity. Moreover, a mechanistic study has been carried out based on DFT calculations and experimental data which have allowed us to propose that the (3+2) cycloaddition reaction follows a sequential Michael addition/Mannich cyclization pathway. The formation of the iminium ion as a result of the condensation between the a,b-unsaturated aldehyde and the catalyst plays an essential role, regarding both reactivity and stereoselectivity. On the other hand we have developed a methodology to carry out a cascade Michael/Henry reaction followed by a sequential dehydration. Starting from simple substrates (2-nitromethylacrilates and a,b-unsaturated aldehydes) and employing a prolinol-derivative catalyst a series of quiral nitrocyclohexadienes have been synthesized.

RARRES3 suppresses breast cancer lung metastasis by regulating adhesion and differentiation

In estrogen receptor-negative breast cancer patients, metastatic relapse usually occurs in the lung and is responsible for the fatal outcome of the disease. Thus, a better understanding of the biology of metastasis is needed. In particular, biomarkers to identify patients that are at risk of lung metastasis could open the avenue for new therapeutic opportunities. Here we characterize the biological activity of RARRES3, a new metastasis suppressor gene whose reduced expression in the primary breast tumors identifies a subgroup of patients more likely to develop lung metastasis. We show that RARRES3 downregulation engages metastasis-initiating capabilities by facilitating adhesion of the tumor cells to the lung parenchyma. In addition, impaired tumor cell differentiation due to the loss of RARRES3 phospholipase A1/A2 activity also contributes to lung metastasis. Our results establish RARRES3 downregulation as a potential biomarker to identify patients at high risk of lung metastasis who might benefit from a differentiation treatment in the adjuvant programme.

Lymphangioleiomyomatosis Biomarkers Linked to Lung Metastatic Potential and Cell Stemness

Lymphangioleiomyomatosis (LAM) is a rare lung-metastasizing neoplasm caused by the proliferation of smooth muscle-like cells that commonly carry loss-of-function mutations in either the tuberous sclerosis complex 1 or 2 (TSC1 or TSC2) genes. While allosteric inhibition of the mechanistic target of rapamycin (mTOR) has shown substantial clinical benefit, complementary therapies are required to improve response and/or to treat specific patients. However, there is a lack of LAM biomarkers that could potentially be used to monitor the disease and to develop other targeted therapies. We hypothesized that the mediators of cancer metastasis to lung, particularly in breast cancer, also play a relevant role in LAM. Analyses across independent breast cancer datasets revealed associations between low TSC1/2 expression, altered mTOR complex 1 (mTORC1) pathway signaling, and metastasis to lung. Subsequently, immunohistochemical analyses of 23 LAM lesions revealed positivity in all cases for the lung metastasis mediators fascin 1 (FSCN1) and inhibitor of DNA binding 1 (ID1). Moreover, assessment of breast cancer stem or luminal progenitor cell biomarkers showed positivity in most LAM tissue for the aldehyde dehydrogenase 1 (ALDH1), integrin-beta 3 (ITGB3/CD61), and/or the sex-determining region Y-box 9 (SOX9) proteins. The immunohistochemical analyses also provided evidence of heterogeneity between and within LAM cases. The analysis of Tsc2-deficient cells revealed relative over-expression of FSCN1 and ID1; however, Tsc2-deficient cells did not show higher sensitivity to ID1-based cancer inhibitors. Collectively, the results of this study reveal novel LAM biomarkers linked to breast cancer metastasis to lung and to cell stemness, which in turn might guide the assessment of additional or complementary therapeutic opportunities for LAM.

Metodología analítica para el control de calidad en ambientadores higiénicos basados en la cuantificación de sus componentes mediante cromatografía de gases acoplada a espectrometría de masas (GC/MS).

Nota técnica para el análisis de compuestos volátiles en fórmulas higiénicas